Estrogen nucleus derivatives for use in the inhibition of sex steroid activity

ABSTRACT

Novel compounds for the inhibition of sex steroid activity for the treatment of both androgen-related and estrogen-related diseases include for example 15- and 16-halo substituted compounds such as: ##STR1## The compounds are characterized by an estrogenic nucleus substituted with a substituent of the formula --R 1  [B--R 2  --] x  L--G 
     wherein at least one of n and G is a polar moiety distanced from a ring carbon of the estrogenic nucleus by at least three intervening atoms: 
     x is an integer from 0--6; 
     R 1  and R 2  are independently either absent or selected from the group consisting of straight- or branched-chain alkylene, straight- or branched-chain alkynylene, straight- or branched-chain alkenylene, phenylene, and fluoro-substituted analogs of the foregoing; and 
     B is either absent or selected from the group consisting of --O-- --Se--, --SO--, --SO 2  --, --NR 3  --, --SiR 3   2 , --CR 3  OR 3  --, NR 3  CO--, NR 3  CS--, --CONR 3  --, CSNR 3  --, --COO--, --COS--, --SCO--, --CSS--, --SCS--, --OCO-- and phenylene (R 3  being hydrogen or lower alkyl).

RELATED APPLICATIONS

This application is a division of application Ser. No. 07/917,915, filedJul. 21, 1992 U.S. Pat. No. 5,204,337, which is a continuation of Ser.No. 07/377,010, filed Jul. 7, 1989 now abandoned, which is acontinuation-in-part of U.S. patent application Ser. No. 07/322,154filed Mar. 10, 1989 now abandoned, and of U.S. application Ser. No.07/265,716 filed Nov. 1, 1988 now abandoned, and of U.S. applicationSer. No. 07/265,150 filed Oct. 31, 1988 now abandoned, the disclosuresof which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

This invention relates to novel inhibitors of sex steroid activity suchas antiestrogen compounds having effective antagonistic capability whilesubstantially lacking agonistic effects. More particularly, certainpreferred embodiments of the invention relate to certain estradiol andnon-steroidal diphenylethylene analogs which have high affinity forestrogen receptors but do not activate such receptors and/or whichinhibit the production of sex steroids or their precursors.

During the treatment of certain sex steroid-dependent diseases, it isimportant to greatly reduce or, if possible, eliminate certain sexsteroid-induced effects. For this purpose, it is desirable both to blockreceptor sites stimulated by sex steroids and also to reduce the amountof sex steroid available to act at these sites. For example, alternativeor concurrent therapy to administration of antiestrogens could involveattempts to block the production of estrogens (e.g. by ovariectomy) suchthat less is available to activate receptor sites. However, prior artmethods for blocking estrogen production insufficiently inhibitestrogen-induced functions. Moreover, it is possible that even in thetotal absence of sex steroids, unoccupied sex steroid receptors may bebiologically active. Hence, antagonists of sex steroids may producegreater therapeutic results than therapy which only inhibits sex steroidproduction. Prior art antagonists, however, often have insufficientaffinity for receptors, and some, although capable of binding thereceptors, may themselves act as agonists and undesirably activate somereceptors and induce the same effects as a sex steroid.

There is, therefore, a need in the art for antiestrogens whicheffectively block estrogen receptors with minimal or no agonisticeffect. Numerous compounds have been tried in the art with mixedresults. Known antiestrogens continue to exhibit undesirable agonisticactivity. See, for instance, Wakeling and Bowler, "Steroidal PureAntioestrogens", J. Endocrinol. (1987) 112, R7-R10. The neteffectiveness of prior art compounds is determined by the balancebetween their agonistic and antagonistic activities. Certain steroidalderivatives similar to those disclosed in the foregoing article, andwhich are stated to have antioestrogenic effect, are set forth in Bowleret al., U.S. Pat. No. 4,659,516.

In U.S. Pat. No. 4,094,994, it is disclosed that the use of certainantiestrogens may inhibit certain human breast tumor cells.

H. Mooridsen et al., Cancer Treatment Review 5, 131-141, (1978),discloses that Tamoxiphen, an antiestrogen, is effective in remission ofadvanced breast cancer in about 30 percent of the women patientstreated.

The combined use of the antiestrogen Tamoxiphen and a luteinizinghormone-releasing hormone agonist, Buserelin, is also known fortreatment of breast cancer. See, for instance, Klijn et al., J. SteroidBiochem, 420, No. 6b, 1381 (1984): The objective remission of suchcancers, however, remains unacceptably low.

It has been found that certain 7α-substituted derivatives of estradiolpossess antiestrogenic activity (Bowler et al., 1985; Eur. PatentApplication 0138504; Wakeling and Bowler, J. Steroid Biochem. 30;141-147, 1988).

In U.S. Pat. No. 4,659,516, Bowler et al. report antiestrogenic activityfor certain 7α substituted derivatives of estradiol.

For a number of years, there has been research for compounds which canefficiently inhibit androgen and/or estrogen formation (e.g. enzymeinhibitors) or for compounds which may suppress androgen or estrogenaction (steroid antagonists), without causing adverse effects to healthytissues.

Recently, estradiol derivatives bearing a carboxyalkyl substituent atthe 7α-position maintained their affinity for the estrogen receptor whenlinked via their carboxy group to agarose or polyacrylamide resin foraffinity chromatography purification of the estrogen receptor (Bucourtet al., J. Biol. Chem. 253: 8221, 1978).

Non steroidal compounds bearing a similar aliphatic side chain have alsobeen found to possess antiestrogenic activity (U.S. Pat. No. 4,732,912).

Some steroid derivatives, such as especially 16-methylene estradiol and16-methylene estrone, have been described as inhibitors of17β-hydroxysteroid dehydrogenase activity (Thomas et al., J. Biol. Chem.258: 11500, 1983).

Prior art methods have not been completely effective in inhibiting sexsteroid synthesis while avoiding undesirable side effects.

Certain nonsteroidal compounds which are stated to have antiandrogeniceffect are described by Furr et al., J. Endocr. 113, R7-R9, 1987.

In U.S. Pat. No. 4,659,695 relates to a method of treatment of prostatecancer for susceptible male animals including humans whose testicularhormonal secretions are blocked by surgical or chemical means, e.g., byuse of an LHRH agonist, e.g., [D-Trp⁶, des-Gly-NH₂ ¹⁰ ]LHRH ethylamide.The treatment includes administering an antiandrogen, e.g., flutamide inassociation with at least one inhibitor of sex steroid biosynthesis,e.g., aminoglutethimide and/or ketoconazole.

U.S. Pat. No. 4,472,382 relates to a method of treating prostate cancerusing the combination of an antiandrogen and an LHRH agonist.

In U.S. Pat. No. 4,386,080 relates to new amide derivatives, and moreparticularly novel acylanilides, possess antiandrogenic properties.

In French, Patent 2528434 and in Jordan and Koch, "Regulation ofProlactin Synthesis in vitro by estrogenic and antiestrogenicderivatives of estradiol and Estrone", Endocrinology 124(4): 1717-1725(1989), antiestrogenic effects are described for certain 11β-long chainsubstituted estradiol derivatives.

In U.S. Pat. No. 3,995,060, U.S. Pat. No. 4,161,540 and U.S. Pat. No.4,139,638, it is disclosed that certain 4'-substituted and 3'-,4'-disubstituted anilides have antiandrogenic properties.

EP Pat. No. 138 504, EP Pat. No. 166 509, EP Pat No. 124 369, EP Pat.No. 160 508, EP Pat. No. 163 416, U.S. Pat. No. 4,732,912, U.S. Pat. No.4,760,061, U.S. Pat. No. 4,751,240, U.S. Pat. No. 4,659,516 and WakelingA. E. and Bowler J., J. Endocr. 112, R7-R10, 1987., and J. SteroidBiochem. 30, 141-147, 1988 disclose that certain long chainsubstitutions onto an estrogenic nucleus may result in compositionsexhibiting antiestrogenic activity.

For a number of years, there has been search for compounds which canefficiently inhibit androgen and/or estrogen formation without causingadverse effects to healthy tissues. More particularly, the inhibition of17β-hydroxysteroid dehydrogenase, which is involved in the biosynthesisof testosterone, androst-5-ene-3β,17β-diol and estradiol, has beenstudied by some workers. Some affinity-label inhibitors for humanplacental estradiol 17β-dehydrogenase have been described (C. C. Chinand J. C. Warren, J. Biol. Chem. 250, 7682-7686, 1975; Y. M. Bhatnagaret al., J. Biol. Chem. 253, 811-815, 1978; C. C. Chin et al., J. Biol.Chem. 255, 3660-3664, 1980; J. L. Thomas and R. C. Strickler, J. Biol.Chem. 258, 1587-1590, 1983).

B. Tobias et al., J. Biol. Chem. 257, 2783-2786, 1982 and R. J. Auchusand D. F. Covey, Biochemistry 25, 7295-7300, 1986 disclose,respectively, the use of 17β-propynyl-substituted progestins andpropynyl-substituted 3-hydroxy-14,15-secoestra-1,3,5(10)-trien-17-one asinhibitors of the 17D-estradiol dehydrogenase.

Thomas J. L. et al., J. Biol. Chem. 258, 11500, 1983 have described that16-methylene estradiol and 16-methylene estrone are inhibitors of17β-hydroxysteroid dehydrogenase activity.

OBJECTS OF THE INVENTION

It is an object of the present invention to provide methods ofinhibiting sex steroid activity. Such methods may be useful in thetreatment of sex steroid-related diseases.

It is another object of the invention to provide a steroidal pureantiestrogen for therapeutic use.

It is another object of the invention to provide compositions capable ofinhibiting sex steroid synthesis, especially estrogen synthesis.

It is another object to provide an antiestrogen having good affinity forestrogen receptors, but substantially lacking undesirable agonisticactivity regarding these receptors and substantially lacking hormonalactivity.

It is another object of the invention to provide a therapeuticantiestrogenic composition useful in the treatment of estrogen-relateddiseases. These diseases include, but are not limited to, breast cancer,uterine cancer, ovarian cancer, endometriosis, uterine fibroma,precocious puberty and benign prostatic hyperplasia.

It is another object of the invention to provide inhibitors of sexsteroid production useful in the treatment of both estrogen- andandrogen-related diseases. Androgen-related diseases include but are notlimited to prostate cancer, acne vulgaris, hirsutism, precociouspuberty, benign prostatic hyperplasia, seborrhea, androgenic alopeciaand sexual deviants. Control of androgen activity may also be useful inmale contraception.

SUMMARY OF THE INVENTION

The present invention provides a method of inhibiting sex steroidactivity in a warm-blooded animal, including humans, comprisingadministering to said animal a therapeutically effective amount of acompound having as part of its molecular structure an estrogenic nucleusof general structure I: ##STR2## wherein the dotted lines representoptional pi bonds and wherein said compound includes as another part ofits molecular structure a side chain substituents onto a ring carbon ofsaid general structure I represented by the formula --R¹ [--B--R²--]_(x) L--G wherein at least one of said side chains is substituted ata ring carbon selected from the group consisting of carbon 14, carbon15, carbon 16 and carbon 17, wherein:

x is an integer from 0 to 6, wherein at least one of L and G is a polarmoiety distanced from said ring carbon by at least three interveningatoms, and wherein:

R¹ and R² are independently either absent or selected from the groupconsisting of straight- or branched-chain alkylene, straight- orbranched-chain alkynylene, straight- or branched-chain alkenylene,phenylene, and fluoro-substituted analogs of the foregoing;

B is either absent or selected from the group consisting of --O--,--S--, --Se--, --SO--, --SO₂ --, --NR³ --, --SiR³ ₂ --, --CR³ OR³ --,--NR³ CO--, --NR³ CS--, --CONR³ --, --CSNR³ --, --COO--, --COS--,--SCO--, --CSS--, --SCS--, --OCO-- and phenylene (R³ being hydrogen orlower alkyl);

L is either a moiety which together with G, forms a heterocyclic ringhaving at least one nitrogen atom or is selected from the groupconsisting of lower alkyl, --CONR⁴ --, --CSNR⁴ --, --NR⁵ CO--, --NR⁵CS--, --NR⁵ CONR⁴ -- ##STR3## --SO₂ NR⁴ --, --CSS--, --SCS--, --(NO)R⁴--, --(PO)R⁴ --, --NR⁵ COO--, --NR⁵ SO₂ --, --O--, --NR⁴ --, --O--,--SO-- and --SO₂ -- (R⁴ and R⁵ being independently selected from thegroup consisting of hydrogen and lower alkyl; and R⁶ being selected fromthe group consisting of hydrogen, nitrile and nitro); and

G is either a moiety which together with L forms a heterocyclic ringhaving at least one nitrogen atom, or is selected from the groupconsisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl, (C₃-C₇)cycloalkyl, bromo(lower)alkyl, chloro(lower)alkyl,fluoro(lower)alkyl, iodo(lower)alkyl, cyano(lower)alkyl,carboxy(lower)alkyl, (lower)alkoxycarbonyl(lower)alkyl, (C₆ -C₁₀)aryl,(C₇ -C₁₁)arylalkyl, di(lower)alkylamino(lower)alkyl andfluoro-substituted analogs of the foregoing.

The invention further provides a method of inhibiting sex steroidactivity in a warm-blooded animal, including humans, comprisingadministering a therapeutically effective amount of at least onecompound having, as part of its molecular structure, a substituted orunsubstituted estrogenic nucleus of general structure I: ##STR4##wherein the dotted lines represent optional pi bonds; and wherein saidcompound includes as another part of its molecular structure a sidechain substitution onto a ring carbon of said general structure I in atleast one position selected from the group consisting of 7, 11, 14, 15,16, 17, (preferably 7α, 15α, or 17α), a side chain of the formula --R¹[--B--R² --]_(x) L--G, as defined above, and wherein general structure Ifurther includes at least one substitution selected from the groupconsisting of 15-halo, 16-halo, 14-hydroxyl, 15-hydroxyl, 14-loweralkyl, 15-lower alkyl (and halogenated or cyano derivatives offoregoing), 14-nitro, 15-nitro, 16-nitro-, 14-alkoxy, 15-alkoxy,16-alkoxy, 14-alkyl (or dialkyl) amino, 15-alkyl (or dialkyl) amino,16-alkyl (or dialkyl) amino, 14-cyano, 15-cyano, 16-cyano, a 15,16bridge atom (preferably carbon) a 14,15 bridge atom (preferably oxygen),16-pi-bonded lower alkyl and 16-pi-bonded lower halogenated alkyl.

Chloro- or bromo-substitution at the 16 position is preferred. Api-bonded lower alkyl substitution at 16 is believed to increaseefficacy of compounds utilized in the foregoing methods, as is analkynyl substitution at the 17αposition. In preferred embodiments R¹⁷ ishydroxyl or in some embodiments R¹⁷α and R¹⁷β together are=0.

The present invention further provides methods for the treatment of sexsteroid-related diseases by administering therapeutically effectiveamounts of sex-steroid activity inhibitors as disclosed herein (with orwithout pharmaceutical carriers or diluents). Sex steroid-relateddiseases include any disease whose onset, maintenance or progress is, atleast in part, dependent upon biological activities induced by sexsteroids such as androgens and estrogens. For example,androgen-dependent diseases include but are not limited to prostatecancer, ache vulgaris, hirsutism, precocious puberty, benign prostatichyperplasia, seborrhea, androgen alopecia and sexual deviance. Controlof androgenic activity may also be useful in male contraception.Estrogen-related diseases include but are not limited to breast cancer,uterine cancer, ovarian cancer, endometriosis, uterine fibroma,precocious puberty and benign prostatic hyperplasia.

The invention further provides a pharmaceutical composition comprising apharmaceutically acceptable diluent or carrier and a therapeuticallyeffective amount of a sex steroid activity inhibitor having anestrogenic nucleus of formula I: ##STR5## substituted at a ring carbonwith at least one side chain represented by the formula --R¹ [--B--R²--]_(x) L--G wherein the constituents of said side chain, the location(and preferred locations) for said chain, and the preferred structuresand substituents of said nucleus are as defined in the above methods forinhibiting sex steroid activity.

The invention further provides a sex steroid activity inhibitingcompound having an estrogenic nucleus of formula I: ##STR6## substitutedat a ring carbon with at least one side chain represented by the formula--R¹ [--B--R² --]_(x) L--G wherein the constituents and locations (andpreferred locations) of said chain, and the preferred structure andsubstituents of said nucleus are as defined above for the methods ofinhibiting sex steroid activity.

The invention further provides an inhibitor of sex steroid activityhaving, as part of its molecular structure, a substituted orunsubstituted non-steroidal estrogenic nucleus of general formula II:##STR7## wherein R⁵ and R⁶ are hydrogen lower alkyl, alkoxy carbonyl,(C₁ -C₂₀) alkanoyl, (C₃ -C₂₀) alkenoyl, (C₃ -C₂₀) alkynoyl, (C₇ -C₁₁)aroyl and alkylsilyl,

wherein dotted lines are optional pi bonds. In some embodiments, theoptional pi bonds are not simultaneously present when aromaticity wouldresult from such simultaneous presence, wherein R¹⁵ is either a directbond from e to the number 5 carbon or a methylene or ethylene linkage tothe number 5 carbon or a lower alkyl substituent, wherein e is selectedfrom the group consisting of carbon, sulfur and nitrogen, q is absent oris a divalent methyl or ethyl moiety; said inhibitor further having aside chain of the formula --R¹ [--B--R² --]_(x) L--G wherein in at leastone of said side chains is substituted at position selected from thegroup consisting of carbon 2, carbon 4, carbon 5, carbon 10, carbon 11,carbon 13, q and on e atom wherein:

x is an integer from 0 to 6, wherein at least one of L and G is a polarmoiety distanced from said ring carbon by at least three interveningatoms, and wherein:

R¹ and R² are independently either absent or selected from the groupconsisting of straight- or branched-chain alkylene, straight- orbranch-carbon 2, carbon 4, carbon 5, carbon 10, carbon 11, carbon 13, qand on e atom wherein:

x is an integer from 0 to 6, wherein at least one of L and G is a polarmoiety distanced from said ring carbon by at least three interveningatoms, and wherein:

R¹ and R² are independently either absent or selected from the groupconsisting of straight- or branched-chain alkylene, straight- orbranched-chain alkynylene, straight- or branched-chain alkenylene,phenylene, and fluoro-substituted analogs of the foregoing;

B is either absent or selected from the group consisting of --O--,--S--, --Se--, --SO--, --SO₂ --, --NR³ --, --SiR³ ₂ --, --CR³ OR³, --NR³CO--, --NR³ CS--, --CONR³ --, --CSNR³ --, --COO--, --COS--, --SCO--,--CSS--, --SCS--, --OCO-- and phenylene (R³ being hydrogen or loweralkyl);

L is either a moiety which together with G, forms a heterocyclic ringhaving at least one nitrogen atom or is selected from the groupconsisting of lower alkyl, --CONR⁴ --, --CSNR⁴ --, --NR⁵ CO--, --NR⁵CS--, --NR⁵ CONR⁴ -- ##STR8## --SO₂ NR⁴ --, --CSS--, --SCS--, --(NO)R⁴--, --(PO)R⁴ --, --NR⁵ COO--, --NR⁵ SO₂ --, --O--, --NR⁴ --, --S--,--SO-- and --SO₂ -- (R⁴ and R⁵ being independently selected from thegroup consisting of hydrogen and lower alkyl; and R⁶ being selected fromthe group consisting of hydrogen, nitrile and nitro); and

G is either a moiety which together with L forms a heterocyclic ringhaving at least one nitrogen atom or is selected from the groupconsisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl, (C₃-C₇)cycloalkyl, bromo(lower)alkyl, chloro(lower)alkyl,fluoro(lower)alkyl, iodo(lower)alkyl, cyano(lower)alkyl,carboxy(lower)alkyl, (lower)alkoxycarbonyl(lower)alkyl, (C₅ -C₁₀)aryl,(C₇ -C₁₁)arylalkyl, di(lower)alkylamino(lower)alkyl, fluoro-substitutedanalogs of the foregoing.

This invention further provides a pharmaceutical composition comprisinga pharmaceutically acceptable diluent or carrier and a therapeuticallyeffective amount of a sex steroid activity inhibitor having, as part ofits molecular structure, a substituted or insubstituted estrogenicnucleus of general structure II, ##STR9## wherein dotted lines areoptional pi bonds; wherein e is selected from the group consisting ofcarbon, sulfur an dnitrogen, q is absent or selected from the groupconsisting of a divalent methyl moiety and a divalent ethyl moiety; R¹⁵is selected from the group consisting of a lower oalkyl subsitutent, adirect bond from e to the number 5 carbon, a methyl linkage from e tothe number 5 carbon; said sex steroid inhibitor further including, asanother part of its molecular structure, a side chain substitution ontoat least one positive said general structure II wherein said side chainhas the general formula --R¹ [--B--R² --] L--G as defined above.

The inhibitor is preferably hydroxy substituted in at least the 3 or 12positions, and is preferably substituted at the 7 position with a C₁ -C₄alkyl. Compounds of formula II above may be used, preferably as part ofpharmaceutical compositions including acceptable diluents or carriers,to treat sex steroid dependent diseases by inhibiting sex steroidactivity.

As used herein, the term "sex steroid activity inhibitor" includes anycompound which suppresses the activity of sex steroids by any mechanismincluding, for example, inhibition of sex steroid synthesis orantagonistic blocking of sex steroid receptors. "Androgen activityinhibitors" and "estrogen activity inhibitors" are sex steroidinhibitors capable of inhibiting the activity of androgens andestrogens, respectively. For example, estrogen activity inhibitorsinclude, but are not limited to antiestrogens which block estrogenreceptors, thereby making them unavailable to estrogen compounds whichcould otherwise activate those receptors. Sex steroid activityinhibitors also include compounds which inhibit the formation ofcompounds capable of activating sex steroid receptors such as inhibitorsof the production of natural sex steroids (e.q. 17β-estradiol) orinhibitors of production of precursors of natural sex steroids. Onemechanism by which these sex steroid production inhibitors may operateis by blocking enzymes which catalyze production of natural sex steroidsor their precursors (e.g. enzymes such as aromatase, 17β-hydroxysteroiddehydrogenase, 3β-hydroxysteroid dehydrogenase and the like).

As used herein, the term "estrogenic nucleus" includes any compoundwhich, in the absence of the side chain substituent specified herein, iscapable of acting as an estrogen as determined by a weight increase ofat least 100 percent over a seven-day period of the uterus ofovariectomized rats treated with the compound in question (0.5 mg twicedaily per 100 grams of body weight) versus a control group ofovariectomized rats. Treatment should start on the day of castration.The precise test, other than any parameters set forth in this paragraph,is that reported in Simard et al., Mol. Endocrinol. 2: 775-784 (1988).

The following conventions apply to structural formulae set forth herein.Unless specifically designated to the contrary, substituents may haveeither α or β stereochemistry or, where valence permits may representone substituent in α position and another in β position. Presence ofoptional pi bonds are independent of each other. All structures includesalts thereof. Atoms of any estrogenic nucleus for which no substituentis shown or described may optionally be substituted or unsubstituted solong as such substitution does not prevent the nucleus from functioningas an "estrogenic nucleus" as defined herein. Those atoms having adefined substituent may optionally be further substituted by othersubstituents where their valence permits such further substitution. Asused herein, the term "lower", when describing a chemical moiety means amoiety having 8 or fewer atoms. For instance, a "lower alkyl" means a C₁to C₈ alkyl. Any moiety of more than two atoms may be straight- orbranched-chain unless otherwise specified.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph illustrating the antiestrogenic activity of one roidalantiestrogen N-n-butyl-N-methyl-11-(3',17'β-dihydroxyestra-1',3',5'(10') trien-7'α-yl)undecanamide as described in E.P. Pat. No. 138504.

FIG. 2 is a graph illustrating that the antiestrogen which is thesubject of FIG. 1 is also a good inhibitor of sex steroid synthesis.

DETAILED DESCRIPTION OF TEE PREFERRED EMBODIMENTS

Preferred methods of treating of sex steroid-related diseases,especially estrogen-related diseases, and preferred methods of blockingestrogen receptors comprise administering to a patient in need of suchtreatment, a therapeutically effective amount of a sex steroid-activityinhibitors as defined above.

Preferred estrogenic nuclei suitable for use in accordance with theinvention include but are not limited to estradiol and derivativesthereof. Other suitable estrogenic nuclei include but are not limited tothose which (as reported in the references set forth below) effect morethan the threshold increase in uterine weight of ovariectomized rats setforth above as defining an estrogenic nucleus (Simard et al., Mol.Endocrinol. 2: 775-784 (1988).

Some preferred estrogenic nuclei include but are not limited to:##STR10## wherein x is a halogen, preferably chlorine or bromine;wherein R₃ and R₄ are independently selected from the group consistingof hydrogen, lower alkyl, lower alkoxy carbonyl, (C₁ -C₂₀), alkanoyl,(C₃ -C₂₀) alkenoyl, (C₃ -C₂₀) alkanoyl and (C₇ -C₂₀) aroyl, alkylsilyl,1-alkyloxy-alkyl and 1-alkyloxy cycloalkyl. ##STR11## wherein R₃ isselected from the group consisting of hydrogen, lower alkyl, loweralkoxy carbonyl, (C₁ -C₂₀), alkanoyl, (C₃ -C₂₀) alkenoyl, (C₃ -C₂₀)alkynoyl and (C₇ -C₁₁) aroyl, alkylsilyl, 1-alkyloxy-alkyl and1-alkyloxy cycloalkyl. ##STR12## wherein R₃ is selected from the groupconsisting of hydrogen, lower alkyl, lower alkoxy carbonyl, (C₁ -C₂₀),alkanoyl, (C₃ -C₂₀) alkenoyl, (C₃ -C₂₀) alkynoyl and (C₇ -C₁₁) aroyl,alkylsilyl, 1-alkyloxy-alkyl and 1-alkyloxy cycloalkyl. ##STR13##wherein R₃ is selected from the group consisting of hydrogen, loweralkyl, lower alkoxy carbonyl, (C₁ -C₂₀), alkanoyl, (C₃ -C₂₀) alkenoyl,(C₃ -C₂₀) alkynoyl and (C₇ -C₁₁) aroyl, alkylsilyl, 1-alkyloxy-alkyl and1-alkyloxy cycloalkyl. ##STR14## wherein R₃ is selected from the groupconsisting of hydrogens, lower alkyl, lower alkoxy carbonyl, (C₁ -C₂₀),alkanoyl, (C₃ -C₂₀) alkenoyl, (C₃ -C₂₀) alkynoyl and (C₇ -C₁₁) aroyl,alkylsilyl, 1-alkyloxy-alkyl and 1-alkyloxy cycloalkyl. ##STR15##wherein the dotted lines are optional double bonds; wherein R₅ and R₆are independently selected from the group consisting of hydrogen, loweralkyl, lower alkoxy carbonyl, (C₁ -C₂₀), alkanoyl, (C₃ -C₂₀) alkenoyl,(C₃ -C₂₀) alkynoyl and C₇ -C₁₁) aroyl, alkylsilyl, 1-alkyloxy-alkyl and1-alkyloxy cycloalkyl. ##STR16## wherein the dotted lines are optionaldouble bonds; wherein R₅ and R₆ are independently selected from thegroup consisting of hydrogens, lower alkyl, lower alkoxy carbonyl, (C₁-C₂₀), alkanoyl, (C₃ -C₂₀) alkenoyl, (C₃ -C₂₀) alkynoyl and (C₇ -C₁₁)aroyl, alkylsilyl, 1-alkyloxy-alkyl and 1-alkyloxy cycloalkyl. ##STR17##wherein q is absent, methylene or ethylene wherein R₅ and R₆ areindependently selected from the group consisting of hydrogens, loweralkyl, lower alkoxy carbonyl, (C₁ -C₂₀), alkanoyl, (C₃ -C₂₀) alkenoyl,(C₃ -C₂₀) alkynoyl and C₇ -C₁₁) aroyl, alkylsilyl, 1alkyloxy-alkyl and1-alkyloxy cycloalkyl.

Preferred sex steroid activity inhibitors result from substitutingestrogenic nucleic with the preferred substituents set forth herein,including the side chain --R¹ --[B--R² ] L--G as defined above.Preferred sex steroid activity inhibitors in accordance with theinvention include but are not limited to:

N-n-butyl-N-methyl-11-(16'α-bromo-3',17'β-dihydroxy-estra-1',3',5'(10')-trien-7'α-yl)undecanamide ("EM 105") ##STR18##N-n-butyl-N-methyl-11-(16'α-bromo-3',17'α-dihydroxy-estra-1',3',5'(10')-trien-7'α-yl)undecanamide ("EM 171") ##STR19##N-n-butyl-N-methyl-11-(16'β-chloro-3',17'β-dihydroxy-estra-1',3',5'(10')-trien-7'α-yl)undecanamide ("EM 139") ##STR20##N-n-butyl-N-methyl-11-(16'α-chloro-3',17'α-dihydroxy-estra-1',3',5'(10')-trien-7'α-yl)undecanamide ("EM 170") ##STR21##N-n-butyl-N-methyl-11-(16'β-iodo-3',17'α-dihydroxy-estra-1',3',5'(10')-trien-7'α-yl)undecanamide ("EM 156") ##STR22##N-n-butyl-N-methyl-11-(3'-hydroxy-17'-oxo-estra-1',3',5'(10'),15'-tetraen-7'α-yl)undecanamide ("EM 112") ##STR23##N-n-butyl-N-methyl-11-(3',17'β-dihydroxy-17'β-ethynyl-estra-1',3',5'(10'),15'-tetraen-7'α-yl)undecanamide ("EM 140") ##STR24##N-n-butyl-N-methyl-11-(3',17'β-dihydroxy-17'α-ethynyl-estra-1',3',5'(10'),14'-tetraen-7'α-yl)undecanamide ("EM 140") ##STR25##N-n-butyl-N-methyl-11-(3',17'β-dihydroxy-15'β,16'β-methylene-estra-1',3',5'(10'),15'-trien-7'α-yl)undecanamide ("EM 136") ##STR26##N-n-butyl-N-methyl-11-(3',17'β-dihydroxy-17'α-ethynyl-estra-15'.beta.,16'β-methylene-estra-1',3',5'(10')-trien-7'α-yl)undecanamide ("EM 138") ##STR27##N-n-butyl-N-methyl-11-(3'-hydroxy-15'β,16'β-methylene-17'oxo-estra-1',3',5'(10')-trien-7'α-yl)undecanamide ("EM 137") ##STR28##N-n-butyl-N-methyl-11-(3'-hydroxy-16'-methylene-17'oxo-estra-1',3',5'-(10')-trien-7'α-yl)undecanamide ("EM 175") ##STR29##N-n-butyl-N-methyl-11-(3',17'β-dibenzoyl-14β,15'β-epoxy-estra-estra-1',3',5'(10')-trien-7'α-yl)undecanamide ("EM 180") ##STR30##N-n-butyl-N-methyl-11-(3',17'β-dibenzoyl-14'α,15'α-epoxy-estra-estra-1',3',5'(10')-trien-7'α-yl) undecanamide ("EM 18 1") ##STR31##N-n-butyl-N-methyl-11-(3',17'β-dihydroxy-estra-1',3',5'(10')-trien-15'α-yl)undecanamide ("EM 108") ##STR32##N-n-butyl-N-methyl-13-(3',17'β-dihydroxy-estra-1',3',5'(10')-trien-17'α-yl)12-tridecynamide ("EM 163") ##STR33##N-n-butyl-N-methyl-14-(3',17'β-dihydroxy-estra-1',3',5,'(10')-trien-17'α-yl)13-octynamide ("EM 195") ##STR34##N-n-butyl-N-methyl-8-(3',17'β-dihydroxy-estra-1',3',5'(10')-trien-17'.alpha.-yl)7-octynamide ("EM 157") ##STR35## N-n-butyl,N-methyl-11-(6'-hydroxy-2'-(4"-hydroxyphenyl)-3'ethyl-indol-N'-yl)undecanamide. ##STR36## N-n-butyl,N-methyl-11-[6'-hydroxy-2'-(4"-hydroxyphenyl)-(1',2'-dihydronaphtalene-3'-yl)undecanamide. ##STR37##N-n-butyl-N-methyl-11-[4,4'-(1,2-diethyl-1,2-ethanydiyl)bis-phenol-3-yl) undecanamide. ##STR38##

When sex steroid activity inhibitors are administered in accordance withthe invention, they are preferably administered as a dosage from about 1mg to about 2000 mg of active expedient (i.e. sex steroid activityinhibitor), per day per 50 kg of body weight, most preferably from about10 mg to about 100 mg per day per kg of body weight.

The sex steroid activity inhibitors are preferably prepared aspharmaceutical compositions together with pharmaceutically acceptablecarriers and diluents. When prepared for parenteral injection, aninhibitor of sex steroid activity is preferably added at a concentrationbetween about 1 mg/ml and about 100 mg/ml (preferably about 2 mg/ml toabout 10 mg/ml) into a carrier preferably selected from the groupconsisting of saline, water, aqueous ethanol, aqueous dimethylsulfoxideand oil.

When a pharmaceutical composition of the invention is prepared for oralingestion, the composition preferably includes at least one inhibitor ofsex steroid activity wherein the total concentration of all suchinhibitors in said pharmaceutical composition is from about 1% to about95% of the composition (by weight), and preferably from about 5% toabout 20%. The composition preferably further includes apharmaceutically acceptable diluent, for example, starch or lactose withor without tartrazine. Slow release pharmaceutical products comprisingthe novel inhibitors of sex steroid activity may be incorporated intoslow release pharmaceutical products which, other than addition of thenovel inhibitors, may be prepared by known methods and administeredorally as well as parenterally.

In the side-chain structure, L is preferably separated from theandrogenic nucleus by at least 3 intervening and preferably 6 atoms. Apolar moiety (G, L or both) is preferably separated from the androgenicnucleus by at least 8 intervening atoms. It is also preferred that theside chain R¹ [--B--R² --]_(x) L--G have between about 7 and 30 carbonatoms.

EXAMPLES OF SYNTHESIS OF PREFERRED INHIBITORS OF SEX STEROID ACTIVITY

INSTRUMENTATION

The IR spectra were taken on a Perkin-Elmer 1310 spectrophotometer.Proton NMR spectra were recorded on a Varian EM-360A (60 MHz, whenspecified) or a Varian XL-200 (MHz) instrument. The followingabbreviations have been used: s, singlet; d, doublet; dd, doublet ofdoublet; t, triplet; q, quadruplet; and m, multiplet. Chemical shiftsare reported in δ values in ppm relative to tetramethysilane (TMS) asinternal standard. Mass spectra (MS) were obtained on a V.G. Micromass16F machine. Thin-layer chromatography (TLC) was performed on 0.25 ramKieselgel 60F254 plates (E. Merck, Darmstadt, FRG). For flashchromatography, Merck-Kieselgel 60(230-400 mesh A.S.T.M.) was used. Allsolvents used in chromatography has been distilled. Unless otherwisenote, starting material and reactant were obtained commercially and wereused as such or purified by standard means. All solvents and reactantspurified and dried were stored under argon. Anhydrous reactions wereperformed under an inert atmosphere, the set-up assembled and cooledunder argon. Organic solutions were dried over magnesium sulfate,evaporated on a rotatory evaporator and under reduced pressure.Anhydrous solvents were prepared in the following way.

    ______________________________________                                        SOLVENT              DISTILLED OVER                                           ______________________________________                                        AMINE, DIMETHYLFORMAMIDE                                                                           CaH.sub.2                                                HEXANE, DICHLOROMETHANE                                                                            P.sub.2 O.sub.5                                          ACETONE              K.sub.2 CO.sub.3                                         BENZENE              LiAlH.sub.4                                              TOLUENE              Na                                                       ETHER, TETRAHYDROFURAN                                                                             LiAlH.sub.4, Na                                                               Benzophenone                                             ______________________________________                                    

EXAMPLE-1 SYNTHESIS OF PREFERRED SEX STEROID ACTIVITY INHIBITORSSynthesis of a starting compound, N-n-butyl,N-methyl-11-(3'-benzoyloxy-17'-oxo-estra-1',3',5'(10')-trien-7'α-yl)undecanamide(9) (SCHEME 1)

19-nor-testosterone acetate 3-enolacetate (2)

In an apparatus supplied with a drierite drying tube, a solution of19-nor-testosterone (1) (100 g; 0.365 mole) in acetic anhydride (200ml), pyridine (32 ml) and acetylchloride (320 ml) was heated at refluxunder magnetic stirring, for 3 h and then concentrated to dryness undervacuum. The dry residue was triturated in absolute ethanol, filtered andwashed with little portions of absolute ethanol. After drying,19-nor-testosterone acetate 3-enolacetate was obtained as a white powder(121.4 g, yield 93%) mp. 176°-177° C. The structure was confirmed byspectroscopic means.

17α-acetoxy-estra-4,6-dien-3-one (3)

To a cooled suspension of enolacetate (121 g; 0.337 mole) in a mixtureof DMF (330 ml) and water (7.2 ml) at 0° C was added, under nitrogen,over a period of 1 h, N-bromosuccinimide (63 g). The resulting solutionwas stirred for an additional 0.5 h at 0° C. Then lithium carbonate(60.8 g) and lithium bromide (30.4 g) were added. The mixture was heatedat 95° C for 3 h and then poured into 1.7 1 of ice-cold water containing165 ml of glacial acetic acid. After stirring during 15 hours, the crude17β-acetoxy-estra-4,6-dien-3-one (3) was filtered, washed with water,dried in a desiccating apparatus and recrystallized twice from isopropylether (72 g, yield 68%, mp 110° C). The structure was confirmed byspectroscopic means.

7α-(11'-acetoxy-undecyl) 17β-acetoxy estra-4-en-3-one (4)

A. Preparation of reagents and solvents

11-bromo undecanol tetrahydro pyranyl ether

11-bromo-undecanol (100 g, 398 mmol) was dissolved in dry ether (768 ml)and the solution was cooled to 0° C. using an ice/H₂ O bath. To thissolution was added HCl gas (2.13 g, 58.4 mmol, 26 ml of HCl/ether).

To this mixture, a solution of 3,4-dihydro-2H-pyran (39.9 g, 43.3 ml)freshly distilled in dry ether (218 ml) was added over a period of 90min. The solution was then stirred over a period of 16 hours at roomtemperature. Afterwards, sodium bicarbonate was added to the mixture.The residue was filtered and the solvent was evaporated under vacuum.

The product was then filtered through basic alumina (250 g, Woelm, gradeII) using petroleum ether (30-60) as solvent (112 g, 81%).

B. Grignard reagent

In a dry three-neck flask (1000 ml) under dry argon, magnesium (12.0 g,494 mmol) was placed and activated with iodine. Magnesium was heatedwith the flame to remove iodine and to dry the apparatus. The system wasthen cooled to -20° C., and a solution of 11-bromo-undecanol tetrahydropyranyl ether (73.8 g, 211 mmol) in dry THF (420 ml) was added dropwise.The mixture was stirred under dry argon during one day at -20° C.

The mixture was cooled to -35° C. (±2° C.) using a dry ice/CCL₄ /acetonebath. The anhydrous cuprous chloride (1.18 g, 12 mmol) was added and themixture was stirred over a period of 0.5 h.

C. Addition of Grignard reagent

After 0.5 h, using the same apparatus mentioned above (Ar, -35° C.), asolution of 17β-acetoxy estra-4,6-diene-3-one (3) (32.0 g, 102 mmol) indry THF (300 ml) was added dropwise over a period of 6 h to the Grignardreagent (red coloration appeared and disappeared). The mixture wasstirred for an additional 1 h and, after removal the cooling bath,acidified (about 0° C.) with acetic acid (40 ml), diluted with water andextracted with ether (3×). The ether solution was washed with asaturated sodium bicarbonate solution and water. The organic layer wasdried over anhydrous magnesium sulfate and evaporated under reducedpressure to dryness.

The residue was dissolved in MeOH (660 ml) and 5N HCl (180 ml), refluxedfor 1 h and 45 min, then concentrated under reduced pressure and cooledin an ice bath. The mixture was then filtered to remove the whiteprecipitate. After the solution had been diluted with water andextracted with methylene chloride (3×), the organic layer was dried overanhydrous MgSO₄ and evaporated under reduced pressure to dryness.Finally, the product (55.9 g, brown oil) was chromatographed on silicagel (Kieselgel 60F254, Merck, 0.063-0.200 mm, 1500 g). Elution withmixtures of methylene chloride and ethyl acetate (4:1 to 1:2 v/v) andthen pure ethyl acetate gave crude 7α-(11'-hydroxy-undecyl)-17β-hydroxyestra-4-en-3-one (34.8 g) which was dissolved in dry pyridine (200 ml)and dry acetic anhydride (200 ml), stirred 17 h at room temperature andthen poured in ice-water. The product was extracted with methylenechloride (3×), washed with 1N hydrochloric acid, water, saturated sodiumbicarbonate and water (3×), dried on anhydrous magnesium sulfate andfiltered. After evaporation of solvent, the mixture (35 g) of 7α- and7β-diacetoxyenones and degradation products of Grignard reagent wereseparated by flash chromatography on silica gel (Kieselgel 60, Merck,230 mesh ASTM, 2.0 kg) developed with a mixture of hexane and diethylether (2:3 v/v). The first product eluted was pure amorphous7α-(11'-acetoxy undecyl) 17β-acetoxy-estra-4-en-3-one, (4) (20.8 g, 39.4mmol, yield from dienone was 39.0%). Further elution gave the 7β-isomer(5) (5.4 g, 10.3 mmol, 10%). All structures were determined byspectroscopic means.

7α-(11'-hydroxy-undecyl) estra-1,3,5(10)-trien-3,17β-diol (6α)

Under dry argon, a solution of 7α-(11'-acetoxy undecyl)17β-acetoxy-estra-4-en-3-one (4) (17.0 g, 32.4 mmol) in dry acetonitrile(150 ml) was added rapidly to a suspension of cupric bromide (14.8 g,65.2 mmol) and mmol) and lithium bromide (2.89 g, 33.6 mmol) in warmacetonitrile (75 ml). The mixture was heated to reflux over a period of30 min and stirred vigorously, and then cooled to room temperature. Asaturated aqueous solution of sodium bicarbonate (50 ml) was added, andthen the organic compound was extracted with ethyl acetate (3×150 ml).The organic layers were washed with water, dried over anhydrousmagnesium sulfate, filtered and evaporated under vacuum to dryness. Theresidue was chromatographed on silica gel (Kieselgel 60F254 Merck0.063-0.200 mm; 1000 g). Elution with hexane-ethyl acetate (1:1 v/v)gave the 7α-(11'-acetoxy-undecyl) estra-1',3',5'(10')-trien-3,17β-diol,17β-acetate (6b) (8.51 g; 50.3%) and the starting product (1.33 g; 15%).

The above diacetate phenol (8.51 g, 16.2 mmol) was dissolved in methanol(90 ml) and sodium hydroxide 30% (w/v) (9 ml). The mixture was refluxedfor 90 min under dry nitrogen. The solution was then concentrated undervacuum and diluted with hydrochloric acid (10% v/v). The mixture wasextracted using ethyl acetate (4×150 ml) and the ethyl acetate extractwas washed with water, dried over anhydrous magnesium sulfate, filteredand evaporated under vacuum. The evaporation gave 7α-(11'-hydroxyundecyl) estra-1,3,5(10)-trien-3,17β-diol (6α) (6.99 g, 98% brut) as ayellow foam, the structure of which was confirmed by spectroscopicmeans.

3-benzoyloxy 7α-(11'-hydroxy undecyl) estra-1,3,5(10)-trien-17β-ol (7)

The above triol (6.99 g; 15.8 mmol) was dissolved in acetone (25 ml) andan aqueous solution of sodium hydroxide (1N, 19.1 ml). The mixture wascooled to 0° C. using an ice/water bath. Benzoyl chloride (2.22 ml, 19.1mmol) was then added dropwise. The mixture was stirred for 40 min at 0°C. and then diluted with water. The solution was extracted using ethylacetate (3×) and the organic layers were washed with a saturated aqueoussolution of sodium bicarbonate and finally with water. The ethyl acetatesolution was dried over anhydrous magnesium sulfate, filtered andevaporated under vacuum to dryness. Then, the residue was immediatelychromatographed on silica gel (Kieselgel, 60F254, 0.063-0.200 mm; 500g). The chromatography was carried out, first, using methylene chlorideas solvent (about 1 liter) and secondly the pure 3-benzoyloxy7α-(11'-hydroxy undecyl) estra-1,3,5(10)-trien-17β-ol (7), colorless oil(6.50 g, 75%) was eluted with methylene chloride-ethyl acetate (5:1about 1 liter and 4:1; v/v). The structure was confirmed byspectroscopic means.

11-(3'-benzoyloxy-17'-oxo-estra-1',3',5'(10')-trien-7'α-yl) undecanoicacid (8)

To a cooled solution of 3-benzoyloxy-7α-(11'-hydroxyundecyl)estra-1,3,5(10)-trien-17β-ol (7) (4.3 g) in acetone (100 ml) wasadded dropwise Jone's reagent (SN-chromic acid solution, 6.7 ml). After30 min, isopropanol (40 ml) was added and the mixture was concentratedunder vacuo. Water was added and the mixture was extracted four timeswith ethyl acetate. The organic layers were washed twice with brine,dried over magnesium sulfate and evaporated to dryness. The crude11-(3'-benzoyloxy-17'-oxo-estra-1',3',5'(10')-trien-7'α-yl) undecanoicacid (8) (3.94 g) was used in the next step without purification.##STR39##N-n-butyl,n-methyl-11-(3'-hydroxy-17'-oxo-estra-1',3',5'(10')-trien-7'.alpha.-yl)undecanamide (9b)

To 11-(3'-benzoyloxy-17'-oxo-estra-1',3',5'(10')-trien-7'α-yl)undecanoic acid (8) (3.94 g, 7.22 mmol), dissolved in anhydrous CH₂ Cl₂(100 ml) and cooled at -10° C. was added tributylamine (2.18 ml, 9.15mmol) and isobutylchloroformate (1.30 ml, 10.0 mmol). The solution wasstirred during 35 min. and N-methylbutylamine (13 ml, 109.7 mmol) wasadded. The mixture was warmed to room temperature and stirred during 1h. Afterward, CH₂ Cl₂ was added and the organic phase was washed with 1NHCl, water, saturated sodium, bicarbonate solution and finally withwater, dried with anhydrous MgSO₄ and the solvent was removed underreduced pressure. The residue was purified by chromatography on silicagel. Elution with mixture of EtOAc/hexane (1.5:8.5 v/v) yielded N-butyl,N-methyl-11-(3'- benzoyloxy-17'-oxo-estra-1,3',5'(10')-trien-7'α-yl)undecanamide (9α) (4.25 g, 96%) as colorless oil; IR ν (neat) 1750, 1725and 1640 cm⁻¹. The above described benzoyloxy amide (341 mg, 0.54 mmol)was dissolved in methanol (10 ml) and cooled at 0° C. Following this 2NNaOH (5 ml) was added and the mixture was stirred during 60 min. at 0°C. The solution was neutralized with 1N HCl and extracted with CH₂ Cl₂.The organic phase was dried with anhydrous MgSO₄ and the solvent wasremoved under reduced pressure. The residue was purified bychromatography on silica gel. Elution with mixture of EtOAc/hexane (3:7v/v) yielded N-butyl,N-methyl-11-(3'-hydroxy-17'-oxo-estra-1',3',4'(10)-trien-7'α-yl)undecanamide (9b) (284 mg, 97%) as colorless oil; ¹ H-NMR δ(CDCl₃) 0.91(s,3H,18'-CH₃), 2.76 app(d,1HJ=16,3 Hz, part of ABX system, 6'-H) 2.96and 2.98 (2s,3H N--CH₃), 3.27 and 3.38 (2t_(app), 2H, J=7.5 Hz, N--CH₂--), 6.63 (broad s, 1H, 4'-H), 6.70 (broad d, 1H, J=8.5 Hz, 2'-H), 7.12(d, 1H, J=8.4 Hz, 1'-H); IR ν_(max) (neat) 3270, 1730, 1615 cm⁻¹ ; MSm/e 523 (M⁺, 100%), 508 (M³⁰ --CH₃, 32%), 142 (C₂ H₄ CON(CH₃)C₄ H₉ ⁺,47%).

16-HALO-ESTRADIOL UNDECANAMIDE (SCHEME 2)

N-n-butyl,N-methyl-11-(3',17'-diacetoxy-estra-1',3',5'(10'),16'-tetraen-7'α-yl)undecanamide (10)

The ketone amide 9b (163 mg, 0.50 mmol) was dissolved in isoprenylacetate (10 ml). p-toluenesulfonic acid (44 mg) was then added and thesolution was distilled to about two-thirds of the original volume in 7 hand was then stirred at reflux for 12 h. Afterwards, the solution wascooled with an ice-water bath and extracted with 50 ml of cooled ether.The ether was washed with a cooled saturated sodium bicarbonate andwater. The organic phase was dried with anhydrous MgSO₄ and the solventwas removed under reduced pressure. The residue was filtered throughalumina (15 mm×50 mm alumina Woehlm neutral, activity II) using amixture of benzene-diethyl ether (3:7 v/v) as eluant. The solvent wasremoved under reduced pressure and, the residue was purified by flashchromatography on silica gel. Elution with mixture of EtOAc/hexane (1:4v/v) yielded the N-butylN-methyl-11-(3',17'-diacetoxy-estra-1',3',5'(10') 16'-tetraen-7'α-yl)undecanamide (10) (244 mg, 80%) as colorless oil; ¹ H-NMR δ_(m) (CDCl₃)0.92 (s,3H,18'-CH₃) 0.92 and 0.95 (2t,3H, J=7.0 Hz, N(CH₂)₃ CH₃) 2.18(s,3H,17'-OCOCH₃), 2.28(s,3H,3'-OCOCH₃), 2.76 app (d1,H,J=16.1 Hz, partof ABX system,6'-H), 2.90 and 2.96 (2s,3H,N--CH₃), 3.26 and 3.35(2t_(app),2H,J=7.6 Hz,N--CH₂ --), 5.52 (m,1H,16'-H), 6.80 (broads,1H,4'-H), 6.85 (dd,1H,J₁ =9.1 Hz and J₂ =3.0 Hz,2'-H), 7.27(d,1H,J=9.1 Hz,1-H); IR ν_(max) (neat) 1750, 1635, 1200 cm⁻¹ ; MS m/e607 (M⁺, 2%), 5(M⁺ --COCH₂, 100%), 550 (M⁺ --COCH₂ --CH₃,13%), 523 (M⁺-2COCH₂,45%), 142 (C₂ H₄ CON(CH₃)C₄. H₉,55%), 129 (C₄ H₉ (CH₃)NCOCH₃⁺,38%), 114 (C₄ H₉ (CH₃)NCO⁺, 60%), 86 (C₄ H₉ (CH₃)N⁺,25%); EXACT MASScalcd for C₃₈ H₅₇ O₅ N 607.4239, found 607.4234.

N-butyl,N-methyl-11-(16'α-chloro-3'acetoxy-17'-oxo-estra-1',3',4'(10')-triene-7'α-yl)undecanamide (11, X═Cl)

To diacetate amide 10, dissolved in 5 ml of acetone, was added asolution of sodium acetate (2.6 equivalents) in acetic acid and water(1:11.3 v/v) and then, was treated with tertbutyl hypochlorite (1 eq.)prepared from t-butanol (4 ml) and Javel water (Javex 6.1%, 50 ml). Theclear solution was warmed to 55° C. and stirred for 1 h. Afterwards, thesolvent was evaporated to dryness. The residue was dissolved in ether(100 ml) and water was added (20 ml). The organic phase was washed withwater, dried with anhydrous MgSO₄ and evaporated to dryness. The residuewas purified by chromatography on silica gel carried out with mixture ofEtOAc/hexane (3:7 v/v) to give the N-butyl,N-methyl-11-(16'α-chloro-3'-acetoxy-17'-oxo-estra-1',3',4'(10')-trien-7'α-yl)undecanamide 11, X═Cl) (115 mg, 89%) as colorless oil; ¹ H-NMR ν(CDCl₃)0.92 and 95 (2t,3H,J=7.0 Hz,N(CH₂)₃ CH₃), 0.96 (s,3H,18'-CH₃), 2.28(s,3H,3'-OCOCH₃), 2.80 app (d,1H,J=16,6 Hz, part of ABX system, 6'-H)2.90 and 2.96 (2s,3H,N--CH₃), 3.24 and 3.35 (2t_(app),2H,J=7.4Hz,--N--CH₂ --), 4.46 (d,1H,J=6.6 Hz,16'β-H), 6.82 (broad s,1H,4'-H),6.86 (dd,1H,J=9.1 Hz and J₂ =,2.6 Hz,2'-H), 7.29 (d,1H,J=9.1 Hz,1'-H);IR ν_(max) (neat) 1750, 1640, 1205 cm⁻¹ ; MS m/e 601, 599 (M⁺, 24%,68%), 142 (C₂ H₄ CON(CH₃)C₄ H₉ ⁺,100%), 114 (C₄ H₉ (CH₃)NCO⁺,93%).

N-butyl,N-methyl-11-(16α-chloro-3',17'-dihydroxy-estra-1',3',5'(10')-trien-7'α-yl)undecanamide ("EM 139") and ("EM 170")

A stirred solution of haloketone amide (11, X═Cl) in anhydroustetrahydrofuran (THF) (10 ml) under argon was chilled to -70° C. with2-propanol/dry ice bath. A solution of 1.0M of lithium aluminium hybride(2 eq.) was then added dropwise. After 30 min, the reaction was allowedto return slowly at 0° C. for 5 rain, then was quenched by the dropwiseaddition of a mixture of THF-EtOAc (5 ml) (1:1 v/v) and acidified atpH˜4 with (10%) HCl. The mixture was stirring for 5 rain at roomtemperature and then extracted with EtOAc. The organic phase was washedwith water, dried on anhydrous Na₂ SO₄ and evaporated under reducedpressure. The residue was chromatographed on silica gel with a mixtureof EtoOAc/hexane (4:6 v/v) as eluant:

N-butyl,N-methyl-11-(16'α-chloro-3',17'α-dihydroxy-estra-1',3',5'(10')-trien-7'α-yl)undecanamide ("EM 170")

(15 mg, 29%) as colorless oil; analytical sample was obtained by HPLCpurification; ¹ H-NMR δ(CDCl₃,400 MHz) 0.79 (s,3H,18'-CH₃), 0.93 and0.96 (2t, 3H,J=7.3 Hz,N(CH₂)₃ CH₃), 2.80 (2H,J₆,6 =15.1 Hz and J₆,7 =4.5Hz, Δδ=24.34 (Hz, system ABX, 6'-H), 2.94 and 2.99 (2s, 3H,N--CH₃), 3.26(dd,J₁ =7.6 Hz and J₂ =7.4 Hz) and 3.32-3.43 (m)-[2H,--N--CH₂ --], 3.71(d,1H,J=4.5 Hz,17'β-H), 4.63 (ddd, 1H, J₁₆,15 =10.2 Hz, J₁₆,17 -=4.5 Hzand J₁₆,17 3.9 Hz, 16'β-H), 6.50 (d, 1H, J=24 Hz, 3'-OH), 6.60 (d,1H,J=2.5 Hz, 4'-H), 6.66 (dd,1H,J₂ =8.4 Hz and J₂ =2.5 Hz, 2'-H), 7.14(d,1H,J=8.5 Hz, 1'-H); IR ν_(max) (neat) 3300, 1615, 1495 cm⁻¹ ; MS m/e561,559 (M⁺, 40%, 100%), 523 (M⁺ -HCl, 20%), 142 (C₂ E₄ CON(CH₃)C₄ H₉ ⁺,44%), 114 (C₄ H₉ (CH₃)CNO⁺, 37%); Exact mass calculated for C₃₄ H₅₄ O₃N³⁵ Cl 559.3785, found 559.3821; and

-N-butyl,N-methyl-11-(16'α-chloro-3',17'β-dihydroxy-estra-1',3',5'(10')trien-7'α-yl)undecanamide ("EM 139")

(25 mg, 55%) as a colorless oil; analytical sample was obtained by HPLCpurification; 1H-NMR δ(CDCl₃, 400 MHz), 0.81 (s,3H, 18'-CH₃), 0.93 and0.96 (2t, 3H,J=7.3 Hz, (CH₂)₃ CH₃), 2.78 (2H, J₆,6 =16.2 Hz and J₆,7=4.5 Hz, Δ⁵ =24.34 Hz, system ABX, 6'-H), 2.94 and 2.99 (2s, 3H,N--CH₃),3.27 (dd, j₁ =7.6 Hz and J₂ =7.5 Hz) and 3.31-3.45 (M)[2H, --N--CH₂ --],3.86 (dd, 1H, J₁₇,17 -_(OH) =3.4 Hz and J₁₇,16 =5.9 Hz, 17'α-H), 4.11(ddd, 1H, J₁₆,15 =10.8 Hz, J₁₆,17 =5.9 Hz and 4.11 (ddd, 1H, J₁₆,15=10.8 Hz, J₁₆,17 =5.9 Hz and J₁₆,15 =2.5 Hz, 16'β-H), 6.56 (d, 1H,J=19.7 Hz, 3'-OH), 6.61 (d, 1H, J=2.5 Hz, 4'-H), 6.66 (dd, 1H, J₁ =8.4Hz and J₂ =2.6 Hz, 2'-H), 7.13 (d, 1H, J=8.4 Hz, 1'-H); IR ν_(max)(neat) 3320, 1615, 1490 cm⁻¹ ; MS m/e 561,559 (M⁺, 38%, 100%), 523 (M⁺-HCl, 16%), 142 (C₂ H₄ CON(CH₃)C₄ H₉ ⁺, 80%), 114 (C₄ H₉ (CH₃)NCO⁺,76%); exact mass calculated for C₃₄ H₅₄ O³⁵ Cl 559.3785 found 559.3825.##STR40## N-n-butyl,N-methyl-11-(16'α-bromo-3'-acetoxy-17'-oxo-estra-1',3',5'-(10'),trien-7'α-yl)undecanamide (11, X═Br)

To the above diacetate 10 (244 mg, 0.40 mmol) dissolved in 10 ml ofacetic acid was added dropwise with stirring within 10 minutes and atroom temperature, a brominating solution composed of 50 mg (0.6 mmol) ofsodium acetate, 1.6 ml of acetic acid, 0.04 ml of water and 63.9 mg(0.02 ml, 0.40 mmol) of bromine. During the course of this reaction, ared coloration appeared and disappeared. To the solution, 50 ml of etherwas added and the organic phase was washed with water (4×50 ml) followedby a saturated sodium bicarbonate solution (2×50 ml) and finally withwater (3×50 ml). The combined phase was dried over anhydrous magnesiumsulfate and the solvent was removed in vacuo. The residue waschromatographed on silica gel (Kieselgel, 60F254, Merck, 0.083-0.200mm). Elution with a mixture of hexane-ethyl acetate (4:1 v/v) yieldedN-butyl,N-methyl-11-(16α-bromo-3'-acetoxy-17'-oxo-estra-1',3',5'(10'),trien-7'-α-yl)undecanamide (11, X═Br) (201 mg, 78%) as colorless oil (201 mg, 78%), ascolorless oil; ¹ H-NMR δ(CDCl₃), 0.94 (s, 3H,18'-CH₃), 2.28 (s, 3H,3'-OCOCH₃), 2.82 app (d,1H,J=16.4 Hz, part of ABX system, 6'-H), 2.90and 2.98 (2s, 3H,N--CH₃), 3.24 and 3.35 (2t_(app), 2H, J=7.7 Hz,--N--CH₂ --), 4.58 (t,1H,J=3.6 Hz, 16β-H), 6.82 (broad s,1H,4'-H), 6.88(dd,1H, J=8.0 Hz and J₂ =4.0 Hz,2'-H), 7.29 (d,1H,J=8.0 Hz, 1'-H); MSm/e 644 (M⁺,7%), 565 (M⁺ --Br, 77%), 522 (M⁺ --Br--COCH₂, 55%), 142 (C₂H₄ CON(CH₃)C₄ H₉ ⁺, 67%), 114 (C₄ H₉ (CH₃)NCO⁺, 66%), 88 (100%).

N-butyl,N-methyl-11-(16'α-bromo-3',17'-dihydroxy-estra-1',3,4'(10')-trien-7'α-yl)undecanamide ("EM 105") and ("EM 171")

A solution of bromoketone amide 11 (X═Br) (295 mg, 0.46 mmol) inanhydrous tetrahydrofuran (10 ml) under argon was chilled to -70° C. anda solution of 1.0M of lithium aluminium hybride in ether (0.92 ml, 0.92mmol) was added dropwise with rapid magnetic stirring. After 30 min, thereaction was quenched by the dropwise addition of a mixture of THF-ethylacetate (1:1 v/v) and acidified by 10% hydrochloric acid. The mixturewas stirring for 5 min at room temperature and then extracted with ethylacetate. The organic phase was washed with water, dried on anhydroussodium sulfate and evaporated to dryness under reduced pressure. Theresidue was purified by chromatography on silica gel. Elution with amixture of hexane-ethyl acetate (7:3 v/v) gave:

N-n-butyl,N-methyl-11-(16'α-bromo-3',17'α-dihydroxy-estra-1',3',5'(10')-trien-7'α-yl)undecanamide ("EM 171")

(63 mg, 21%) as colorless oil; ¹ H-NMR δ(CDCl₃, 400 MHz) 0.81 (s, 3H,18'-CH₃), 0.93 and 0.96 (2t, 3H,J=7.3 Hz,N(CH₂)₃ CH₃), 2.79 (2H,J6,6 Hz,J₆,7 =4.7 Hz, =Δδ=24.34 Hz, system ABX,6'-H), 2.94 and 2.99(2s,3H,N--CH₃), 3.27 (dd,2H,J₁ =7.7 Hz and J₂ =7.5 Hz, --N--CH₂ --),3.31-3.44 (m,2H,--N--CH₂ --), 3.66 (dd,1H,J₁₇,17 =1.4 Hz, J₁₇,16 =4,3Hz, 17'α-H), 4.68 (dt,1H,J₁₆,17 =4,3 Hz, m, J₁₆,15 =9.7 Hz,16'α-H), 6.60(d,1H,J=2.4 Hz, 4'-H), 6.65 (dd, 1H,J=8.5 Hz and J₂ =2.5 Hz, 2'-H), 7.14(d,1H,J=8.5 Hz, 1'-H); IR ν_(max) (neat) 3300, 1615, 1495 cm⁻¹ ; MS m/e605,603 (M⁺, 17%), 523 (M⁺ -HBr, 81%), 142 (C₂ H₄ CON(CH₃)C₄ H₉ ⁺,100%), 114 (C₄ H₉ (CH₃)NCO⁺,97%); Exact mass calculated for C₃₄ H₅₄ O₃N⁷⁹ Br 603.8289, found 603.3304. and

N-n-butyl,N-methyl-11-(16'α-bromo-3',17'β-dihydroxy-estra-1',3',5'(10')-trien-7α-yl)undecanamide ("EM 105")

(170 mg, 50%) as a colorless oil; analytical sample was obtained by HPLCpurification; ¹ H-NMR δ(CDCl₃, 400 MHz), 0.80 (s,3H,18,--CH₃), 0.93 and0.96 (2t,3H,J=7.3 Hz,N(CH₂)₃ CH₃), 2.80 (2H,J₆,6 =16.4,J₆,7 =4.6 Hz,Δδ=24.34 Hz, system ABX, 6'-H), 2.94 and 2.99 (2s,3H,N--CH₃), 3.27 (dd,2H,J₁ =7.7 Hz and J₂ =7.5 Hz --N--CH₂ --) 3.31-3.45 (m,2H,--N--CH₂ --)4.02 (dd,1H,J₁₇,17 =3.7 Hz, and J₁₇,16 =6.1 Hz, 17'α-H), 4.15(ddd,1H,J₁₆,15 =10.2 Hz, J₁₆,17 =6.1 Hz and J₁₆ 15 =2.9 Hz, 18'β-H),6.61 (d,1H,J=2.5 Hz, 4'-H), 6.66 (dd,1H,J=8.4 Hz and J₂ 2.5 Hz, 2'-H),7.12 (d,1H,J=8.4 Hz, 1'-H); IR ν_(max) (neat) 3320, 1610, 1490 cm⁻¹ ; MSm/e 605,603 (M⁺, 29%), 523 (M⁺ -HBr, 100%), 142 (C₂ H₄ CON(CH₃)C₄ H₉ ⁺,70%), 114 (C₄ H₉ (CH₃)NCO⁺, 60%); Exact mass calculated for C₃₄ H₅₄ O₃N⁷⁹ Br 603 3289, found 603.3289.

N-butyl,N-methyl-11-(16'α-iodo-3',17'α-dihydroxy-estra-1',3',5'(10')-trien-7'α-yl)undecanamide ("EM 156")

Under argon atmosphere, a mixture of 16α-bromodiol EM 105 (55 mg, 0.091mmol) and dry sodium iodide (136 mg, 0.91 mmol) in freshly ethyl methylketone (25 ml) was refluxed in darkness during 12 h. Afterwards, thesolvent was evaporated, water was added and the product was extractedwith ethyl acetate. The organic phase was washed with 5% sodiumthiosulfate and with water, dried over anhydrous sodium sulfate andconcentrated to dryness under reduced pressure. The residue was purifiedby chromatography. Elution with a mixture of hexane-ethyl acetate (1:1,v/v) gave a mixture of starting material and iodo compound (52:48) ofwhich HPLC separation afforded N-butyl,N-methyl-11,(16'-α-iodo-3',17'β-dihydroxy-estra-1',3',5'(10')-trien-7'α-yl)undecanamide ("El 156") (21 mg, 36%) as colorless oil; ¹ H-NMR δ(CDCl₃,400 MHz) 0.78 (s,3H,18'-CH₃), 0.93 and 0.96 (2t,3H,J=7.3 Hz, N(CH₂)₃CH₃), 2.79 (2H,J₆,6 =16.5 Hz J₆,7 =4.4 Hz,Δδ=24.34 Hz, system ABX,6'-H), 2.94 and 2.99 (2s,3H,N--CH₃), 3.27 (dd,2H,J₁ 32 7.6 Hz and J₂=7.5 Hz, --N--CH₂) 3.32-3.44 (m, 2H N--CH₃), 4.09-4.17 (m, 2H, 16'αH and17α-H), 6.60 (d,1H,J=2.4 Hz, 4'-H), 6.65 (dd,1H,J=8.4 Hz and J₂ =2.4 Hz,2'-H), 7.13 (d,1H,J=8.4 Hz, 1'-H); IR ν (neat) 3310, 1610, 1490 cm⁻¹ ;MS m/e 651 (M⁺, 8%), 523 (M⁺ -HI, 100%), 508 (M⁺ --HI--CH₃,38%) 142 (C₂H₄ CON(CH₃)C₄ H₉ ⁺, 54%), 114 (C₄ H₉ (CH₃)NCO⁺, 49%); Exact masscalculated for C₃₄ H₅₄ O₃ NI-HI 523.4028, found 523.4028.

Efficacy of an antiestrogen synthesized in accordance with Example 1

Compound "EM 139" synthesized as shown in Scheme 2 above is an estrogenactivity inhibitor. "EM 139" has been tested both for efficacy in actingas an antiestrogen by blocking estrogen receptors without substantiallyactivating those receptors, (see FIG. 1 and explanation below) and forefficacy in inhibiting 17β-hydroxysteroid dehydrogenase, (see FIG. 2 andexplanation below) an enzyme which catalyzes reactions involved in thesynthesis of both androgens and estrogens (hereinafter referred to as"17β-HSD").

The antiestrogenic activity of "EM 139" was measured as shown in FIG. 1as its ability to inhibit the estradiol-induced stimulation of uterineweight in adult female ovariectomized Balb/c mice (body weight=19-20 g)sacrificed five days after ovariectomy. "Ovariectomized mice injectedwith estradiol and no antiestrogen had a resultant uterine weight asshown by the shaded area designated "OVX+E₂ " in FIG. 1. The baselineuterine weight for a control group of ovariectomized mice injected withneither estradiol nor antiestrogen is represented in FIG. 1 by "OVX".The antiestrogen "EM 139" , and estradiol dissolved in ethanol wereinjected subcutaneously in the appropriate test groups in a solution of0.9% (w/v) sodium chloride and 1% (w/v) gelatin at differentconcentrations of "EM 139" (as noted along the X axis of FIG. 1.) Adosage of 0.2 ml of the foregoing preparation, was administered twicedaily, starting on the day of ovariectomy for a total of 9 injections.Estradiol was injected at the dose of 0.01 μg in 0.2 ml, twice daily,starting on the morning after ovariectomy for a total of 8 injections.

After sacrifice, the uteri were rapidly removed, freed from fat andconnective tissue and weighed. Results shown in FIG. 1 are the means±SEM of groups of 9-10 mice. As may be seen from FIG. 1, EM 139 washighly potent to reduce estradiol-induced uterine weight gain.

To test the effect of "EM 139" on the inhibition of sex steroidformation, its effect in inhibiting 17β-hydroxysteroid dehydrogenasecatalysis (specifically, conversion of estradiol to estrone) wasobserved. The reaction was followed by monitoring formation of thereduced form of nicotiramide adenine dinucleotide ("NADH"); (at 340 nm).The rate of conversion of cofactor NAD (the oxidized form) to NADHvaries directly with the rate of estradiol conversion to estrone. Theability of "EM 139" to inhibit estrone production is indicative of itsability to inhibit the activity of 17β-hydroxysteroid dehydrogenase(Thomas et al. J. Biol. Chem. 258: 11500-11504, 1983).17β-hydroxysteroid dehydrogenase (17β-HSD) was purified to homogeneityfrom human placenta. A reaction vessel was prepared containing 1 μg17β-HSD, 5 mM NAD, 20 μM 17β-estradiol, and the concentrations of thetest compound "EM 139" which are indicated along the X-axis of FIG. 2 in1.0 ml of a mixture of Tris-HCl (50 mM), EDTA (2 mM), NaN₃ (5 mM). ThepH was 7.5. The reaction was allowed to proceed at 25° C. for 15 min.Formation of NADH was measured at 340 nm. As shown by FIG. 2, increasingconcentrations of EM 139 significantly inhibited the reaction (shown inFIG. 2 as a decrease in formation of NADH).

EXAMPLE 2 N-n-BUTYL,N-METHYL-11-(3',17'β-DIHYDROXY-17'α-ETHINYL-ESTRA-(1',3',5'-(10'),15'-TETRAEN-7'α-YL) UNDECANAMIDE ("EM 123") (Scheme 3)

N-n-butyl, N-methyl-11-(3'-benzoyloxy-17'-ethylenedioxyestra-1',3',5'-(10')-,trien-7'α-yl) undecanamide (12)

A mixture of N-n-butyl, N-methyl-11-(3'-benzoyloxy-17'-oxoestra-1',3',5'(10')-trien-7'-α-yl) undecanamide (9α) (3.63 g), ethyleneglycol (215 ml), p-toluenesulfonic acid (530 mg) and anhydrous benzene(250 ml) was refluxed with a Dean-Stark apparatus during 24 h. Aftercooling, the mixture was poured in water and extracted three times withether. The organic layer was washed with a saturated sodium bicarbonatesolution, and brine (3×), dried on magnesium sulfate and evaporated todryness. The residue was purified by flash chromatography on silica-gel(Kieselgel 60, Merck, 230 mesh ASTM, 300 g). Elution with a mixture ofhexane-ethyl acetate (6:4 v/v) gave pure N-butyl,N-methyl-11-(3'-benzoyloxy-17'-ethylenedioxy estra-1',3',5'(10'),trien-7'α-yl) undecanamide (3.58 g, 92%) as an oil, the structure ofwhich was confirmed by spectroscopic means.

N-n-butyl,N-methyl-11-(3'-benzoyloxy-16'α-bromo-17'-ethylenedioxy-estra-1',3',5'(10'),trien-7'α-yl)undecanamide (13)

To the above ethylenedioxy amide 12 (370 mg, 0.55 mmol) in anhydroustetrahydrofuran (10 ml) cooled at 0° C. was added dropwise under argon,a solution of pyridinium bromide perbromide (406 mg, 1.36 mmol) in 7 mlof the same solvent. After stirring during 1.5 h at 0° C., sodium iodide(300 mg) was added and the solution was stirred for 25 min. Afterwards,a solution of sodium thiosulfate (10%, v/v, 10 ml) and pyridine (0.5 ml)was added and the mixture was stirred for an additional 4 h and thenpoured into water and extracted three times with ether. The organiclayers were washed with 1N hydrochloric acid, water, saturatedbicarbonate solution and water (3×), dried on magnesium sulfate andevaporated to dryness. The residue was chromatographed on silica-gel (50g). Elution with a mixture of hexane-ethyl acetate (4:1 v/v) gave pureN-n-butyl,N-methyl-11-(3'-benzoyloxy-16'α-bromo-17'-ethylenedioxy-estra-1',3',5'(10'),trien-7'α-yl)undecanamide (13) (313 mg, 76%) as colorless oil; IR ν_(max) (neat),1730, 163 1595 and 1255 cm⁻¹ ; ¹ H NMR, 0.93 (3H, s, 18'-CH₃), 2.28 (2H,2d, J=7.5 and 2.6 Hz, --CH₂ CON--), 2.90 and 2.95 (3H, 2s, --N--CH₃),3.24 and 3.35 (2H, 2t, J=7.3 Hz, --N--CH₂ --), 3.85 and 4.35 (4H, m,--OCH₂ CH₂ O--), 4.56 (1H, m, H--C.16'), 6.91 (1H, d, J=2.2 Hz,H--C.4'), 6.98 (1H, dd, J=8.4 and 2.2 Hz, H--C.2'), 7.32 (1H, d, J=8.4Hz, H--C.1'), 7.49 (2H, t_(app) : J=7.0 Hz H--C.3" and H--C.5"), 7.63(1H, t_(app)., J=7.0 Hz, H--C.4") and 8.17 (2H, d, J=7.0 Hz, H--C.2"),and H--C.6"), MS m/e, 671 (M⁺ -Br,11%), 114 (C₄ H₉ (CH₃)NCO⁺, 13%), 105(C₆ H₅ CO⁺, 100%), 86 (C₄ H₉ (CH₃)N⁺, 10%), 77 (C₆ H₅, 25%).

N-n-butyl, N-methyl-11-(3'-hydroxy-17'-oxo-estra-1',3',5'(10'),15'-tetraen-7'α-yl) undecanamide "(El{112)"

To a solution of the bromoketal (13) (517 mg, 0.69 mmol) in anhydrousdimethyl sulfoxide warmed at 73° C., under argon, was addedpotassium-t-butoxide (1.55 g, 13.8 mmol). The mixture was stirred for 5h at this temperature and then cooled, poured in ice-water, acidifiedwith 1N hydro-chloric acid and extracted three times with ethyl acetate.The organic layers were washed with water (3×), dried on magnesiumsulfate and evaporated to dryness. The residue was dissolved in acetone(30 ml), water (7 ml) and p-toluenesulfonic acid (60 mg) was added. Theresulting solution was stirred for 5 h at room temperature and thenpoured into water. The organic compound was extracted three times withether, washed with a saturated sodium bicarbonate solution and water(3×), dried on magnesium sulfate and evaporated to dryness. The residuewas purified by "flash chromatography" (100 g). Elution with a mixtureof hexane-ethyl acetate (1:1 v/v) Eave the pure N-butyl,N-methyl-11-(3'-hydroxy-17'-oxo-estra-1',3',5'(10'), 15'-tetraen-7'α-yl)undecanamide "EM 112" (178 mg, 49%) as colorless oil; IR ν_(max) (neat),3290, 1695, 1620 and 1600 cm⁻¹ ; ¹ H NMR, 0.92 and 0.95 (3H, 2t, J=7.3and 7.0 Hz, --N--(Ch₂)₃ (CH₃), 1.11 (3H, s, 18'-CH₃), 2.32 (2H, td,J=2.5 and 7.0 Hz, H--C.2), 2.94 and 2.99 (3H, 2s, N--CH₃), 3.27 and 3.38(2H, 2t, J=7.7 and 7.3 Hz, --N--CH₂ --), 6.11 (1H, dd, J=6.2 and 3.3 Hz,H--C.15'), 6.66 (1H, d, J=2.6 Hz, H--C.4'), 6.71 (1H, dd, J=8.4 and 2.6Hz, H--C.2'), 7.13 (1H, d, J=8.4 Hz, H--C.1'), 7.60 (1H, dd, J=6.2 and1.5 Hz, H--C.16') and 7.70 (1H, broad s, w_(1/2) =16 Hz, OH), MS m/e,521 (M⁺, 53%), 507 (M⁺ --CH₂, 9%), 506 (M⁺ --CH₃, 7%), 142 (C₂ H₄CON(CH₃)C₄ H₉ ⁺, 25%), 114 (C₄ H₉ (CH₃)NCO⁺, 60%) and 86 (C₄ H₉ (CH₃)N+,22%), 44 (100%).

N-n-butyl,N-methyl-11-(3',17'β-dihydroxy-17'α-ethinyl-estra-1',3',5'-(10'),15'-tetraen-7'α-yl) undecanamide ("EM 123")

To hexanes (1 ml) cooled at 0° C., were added trimethylsilylacetylene(0.112 ml), n-butyllithium 1.6M in hexanes (0.25 ml), few drops ofanhydrous THF and finally, a slowly addition of a solution of enoneamide EM 112 (57 mg) in anhydrous THF (1.2 ml). The mixture was stirredfor 30 min at 0° C. After addition of a saturated ammonium chloridesolution, the mixture was extracted with ethyl acetate (3×). The organiclayers were washed with water and brine, dried over magnesium sulfateand filtered. The solvent was removed under reduced pressure. To theresidue (61 mg) dissolved in methanol, a 5N potassium hydroxide solution(0.177 ml) was added and the mixture refluxed for 50 min. After coolingand addition of a saturated ammonium chloride solution, the mixture wasextracted three times with ethyl acetate. The organic layers were washedwith brine, dried over magnesium sulfate and filtered. The organicsolvent was removed under reduced pressure. The residue waschromatographied on silica-gel (5 g). Elution with a mixture of hexanes:ethyl acetate (7:3 v/v) gave N-butyl,N-methyl-11-(3',17'β-dihydroxy-17'α-ethinyl-estra-1',3',5'-(10'),15'-tetraen-7'α-yl)undecanamide("EM 123") (34 mg, 63%); IR ν_(max) (neat), 3290, 2150, 1620 and 1600cm⁻¹ ; ¹ H NMR, 0.92 and 0.95 (3H, 2t, J=7.3 and 7.0 Hz, N--(CH₂)₃ CH₃),0.95 (3H, s, 18'-CH₃), 2.32 (2H, td, J=7.0 and 2. Hz, --CH₂ CON--), 2.66(1H, s, --CR), 2.93 and 2.98 (3H, 2s, N--CH₃), 3.27 and 3.38 (2H, t,J=7.0 H z , --N--CH₂ --), 5.78 (1H, dd, J=5.9 and 3.3 Hz, H--C.15'),6.05 (1H, dd, J=5.9 and 1.5 Hz, H--C.16'), 6.62 (1H, d, J=2.5 Hz,H--C.4'), 6.67 (1H, dd, J=8.4 and 2.6 Hz, H--C.2') and 7.13 (1H, d,J=8.4 Hz, H--C.1') ppm; MS m/e 547 (M⁺, 12%), 142 (C₂ H₄ CON(CH₃)C₄ H₉⁺, 21%) 114 (C₄ H₉ (CH₃)NCO⁺, 50%), 88 (100%) and 86 (C₄ H₉ (CH₃)N+,34%).

EXAMPLE 3 16β-CYCLOPROPYL DERIVATIVES

N-n-butyl, N-methyl-11-(17'-oxo-3'-hydroxy-15'α,16'α-methylene-estra1',3',5'(10')-trien-7'α-yl) undecanamide (14)

A solution of the phenol-enone FM 112 (101 mg; 0.19 mmol) dissolved inanhydrous pyridine (15 ml) and acetic anhydride (10 ml) was stirred atroom temperature for 20 h. The mixture was into ice-water, thenextracted three times with ether. The organic layers were washed with 1Nhydrochloric acid, water and a saturated sodium bicarbonate solution andwater, dried on magnesium sulfate and evaporated to dryness. The residuewas purified by "flash chromatography" on silica-gel (20 g). Elutionwith a mixture of hexane-ethyl acetate (7:3 v/v) gave the N-butyl,N-methyl-11-(17'-oxo-3'-acetoxy-estra-1',3',5'(10'),15'-tetraen-7'α-yl)undecanamide.

To this and palladium (II) acetate (11 mg) in ether (25 ml) an etherealdiazomethane solution (prepared from 1 g of diazald) was added dropwiseat 0° C. with continuous stirring during 10 min. After evaporation, theresidue was dissolved in methanol (50 ml) and cooled to 0° C. 2N sodiumhydroxide solution (1 ml) was added and after 75 min. of stirring themixture was neutralized with 1N hydrochloric acid, extracted three timeswith ether. The organic layers were washed with brine, dried onmagnesium sulfate and evaporated to dryness. The residue was purified byHPLC to give N-butyl, N-methyl-11-(17'-oxo-3'-hydroxy-15'β,16'β-methylene-estra-1',3',5'(10')-trien -7'α-yl) undecanamide (14) (79mg, 76%) as a colorless oil. IR ν_(max) (neat) 3260, 1705, 1610 and 1570cm⁻¹ ; ¹ H NMR (400 MHz) 0.93 and 0.96 (3H, 2t, J=7.3 Hz, N(CH₂)₃ CH₃),0.99 (3H, s, 18'-CH₃), 1.98 (1H, td, J=8.3 and 3.96 Hz, H--C.16'), 2.80(1H, d, J=16.6 Hz, Hβ--C.6'), 2.94 and 2.98 (3H, 2s, N--CH₃), 3.27 (1H,dd, J=7.58 and 6.66 Hz) and 3.38 (1H, m) (both are --N--CH₂ --), 6.64(1H, d, J=2.6 Hz, H--C.4'), 6.66 (1H, dd, J=8.2 and 2.6 Hz, H--C.3') and7.10 (1H, d, J=8.2 Hz, H--C.1') ppm; MS m/e 535 (M⁺, 74%), 522 (M⁺--CH₂, 49%), 129 (C₄ H₉ (CH₃)NCOCH₃ ⁺, 37%), 114 (C₄ H₉ (CH₃)NCO⁺, 67%)and 88 (100%).

N-n-butyl, N-methyl-11-(3',17'β-dixydroxy-15'β,16'β-methylene-estra-1',3',-5'(10')-trien-7'α-yl) undecanamide ("EM136")

To the cyclopropylketone 14 (10 mg, 18.7 μmol) dissolved in methanol (8ml) was added sodium borohydride (1.5 mg). The mixture was stirred atroom temperature for 18 h. After addition of water, the mixture wasconcentrated under reduced pressure. The residue was diluted with waterand extracted three times with ethylacetate. The organic layers werewashed with brine, dried over magnesium sulfate and filtered. Theorganic solvent was removed under reduced pressure and the residue waspurified by "flash chromatography" on silica-gel (5 g). Elution with amixture of hexanes: ethyl acetate (5:5 v/v) gave N-butyl,N-methyl-11-(3',17'α-dihydroxy15'β,-16'β-cyclopropyl-estra-1',3',5'(10')-trien-7'α-yl) undecanamide("EM 136"), as a colorless oil; IR ν_(max) (neat) 3300, 1615, 1580 and1450 cm⁻¹, ¹ H NMR (400 MHz), 0.31 (1H, dd, J=14.0 and 7.8 Hz, H--C.1")0.83 (3H, s, 18'-CH₃), 0.93 and 0.96 (3H, 2t, J=7.3 Hz, N(CH₂)₃ CH₃),2.77 (1H, d, J=17.1 Hz, Hβ--C.6'), 2.94 and 2.98 (3H, 2s, N--CH₃), 3.27(1H, dd, J=7.7 and 7.5 Hz) and 3.39 (1H, m) (both are --N--CH₂), 4.09(1H, broad s, w=10 Hz, H--C.17'), 6.64 (2H, m, H--C.4' and H--C.2') and7.11 (1H, d, J=8.3 Hz, H--C.1') ppm; MS m/e 537 (M⁺, 18%), 519 (M⁺ --H₂O,56%), 504 (M⁺ -H₂ O--CH₃, 100%), 142 (C₂ H₄ CON(CH₃)C₄ H₉ ⁺, 70%), 114(C₄ H₉ (CH₃)NCO⁺, 50%) and 86 (C₄ H₉ (CH₃)N⁺, 33%).

N-n-butyl,N-methyl-11-(3',17'β-dihydroxy-17'α-ethinyl-15'β,16'β-methylene-estra-1',3',5'(10')-trien-7'α-yl)undecanamide ("EM 138")

To hexanes (500 μl ) cooled at 0° C., were added trimethylsilylacetylene(54.6 μl ), 1.6M n-butyl lithium in hexanes (120.4 μl ), few drops ofanhydrous THF and finally, a slowly addition of a solution of thecyclopropyl ketone "EM 136" (25.8 mg) in anhydrous THF (350 μl ). Themixture was stirred for 75 min at 0° C. After addition of a saturatedammonium chloride solution (1 ml), the mixture was extracted three timeswith ethyl acetate. The organic layers were washed with water and brine,dried over magnesium sulfate and filtered. Tee solvent was removed underreduced pressure. To the residue dissolved in methanol (900 μl), a 5Npotassium hydroxide solution (70 μl) was added and the mixture refluxedfor 30 min. After cooling and addition of a saturated ammonium chloridesolution (1 ml), the mixture was extracted three times with ethylacetate. The organic layers were with washed with brine, dried overmagnesium sulfate and filtered. The organic solvent was removed underreduced pressure. The residue was purified by "flash chromatography" onsilica-gel (5 g). Elution with a mixture of hexanes: ethyl acetate (5:5v/v) gave N-butyl,N-methyl-11-(3',17'β-dihydroxy-17'α-ethinyl-15'β,16'β-cyclopropyl-estra-1',3',5'(10')-trien-7'α-yl)undecanamide ("EM 138") (12 mg, 44%) as a colorless oil; IR ν_(max)(neat) 3590, 3300, 1620, 1600 and 1450 cm⁻¹ ; ¹ H NMR (400 MHz), 0.39(1H, ddd, J=14.6 and 7.9 Hz, H--C.1'), 0.93 and 0.96 (3H, 2t, J=7.4 and7.3 Hz, --N(CH₂)₃ --CH₃), 0.96 (3H, s, 18'-CH₃), 2.70 (1H, s, --C CH),2.77 (1H, d, J=16.5 Hz, Hβ--C.6'), 2.94 and 2.98 (3H, s, N--CH₃), 3.27(1H, dd, J=7.7 and 7.6 Hz) and 3.38 (1H, m) (both are N--CH₃ --), 6.42(1H, m, OH), 6.65 (2H, m, H--C.4' and H--C.2') and 7.12 (1H, d, J=8.3Hz, H--C.1') ppm; MS m/e 561 (M⁺, 15%), 142 (C₂ H₄ CON(CH₃)C₄ H₉ ⁻⁺, 66%), 114 (C₄ H₉ (CH₃)CO⁺, 53%), 88 (100%) an 86 (C₄ H₉ (CH₃)N⁺, 35%).##STR41##

17α-ALKYNYLAMIDE ESTRADIOLS

General Procedure for Ester Formation (scheme 4 A)

In anhydrous conditions under argon atmosphere, bromo acid (17 mmol) wasdissolved in dry CH₂ Cl₂ (30 ml), oxalyl chloride (12 ml) was added andthe reaction was stirred 2 h at room temperature. Then, dry benzene wasadded to mixture and solvent was evaporated under reduced pressure (2×)and dried under vacuum. This crude product was dissolved in dry CH₂ Cl₂(20 ml) and added at 0° C. to a solution of 3-methyl 3-oxetanemethanol(17 mmol), CH₂ Cl₂ (7 ml) and pyridine (1.4 ml). The reaction was keepedat this temperature for 4-8 h. Thereafter, mixture was diluted with CH₂Cl₂, washed with NaHCO₃ (10%, w/v) and organic phase was dried overMgSO₄. After removal of solvent, residue was purified by chromatography(hexane-ethylacetate-triethylamine/80:20:1, v/v/v) to afford bromoester.

6-bromo hexanoate ester of 3-methyl-3-hydroxymethyloxetane. (15). Lightyellow liquid (91% yield); IR ν (neat) 2930, 2860, 1725, 1450, 1370,1160 cm⁻¹ ; NMR-60 δ(CDCl₃) 1.31 (s, 3H), 1.1-2.1 (m, 6H), 2.36 (t,J=6.0 Hz, 2H), 3.36 (t, J=6 Hz, 2H), 4.13 (s, 2H), 4.41 (AB systemΔν=8.3, J=6 Hz, 4H).

9-bromo nonanoate ester of 3-methyl-3-hydroxymethyl oxetane (16).Colorless liquid (86% yield); IR ν(neat) 2920, 2840, 1725, 1450, 1370,1150 cm⁻¹ ; NMR-60 δ(CDCl₃) 1.31 (s, 11H), 1.2-2.2 (m, 4H), 2.40 (t,J=6.0 Hz, 2H), 3.45 (t, J=6.0 Hz, 2H), 4.20 (s, 2H), 4.48 (AB systemΔν=8.2, J=6.0 Hz, 4H).

11-bromo undecanoate ester of 3-methyl-3-hydroxymethyl oxetane (17).Colorless liquid (85% yield); NMR-60 δ(CDCl₃) 1.33 (s, 15H), 1.0-2.0 (m,4H), 2.30 (t, J=6.0 Hz, 2H), 3.35 (t, J=6.0 Hz, 2H), 4.12 (s, 2H), 4.40(AB system Δν=8.2, J=6.0 Hz, 4H).

12-bromo dodecanoate ester of 3-methyl-3-hydroxymethyl oxetane (18).Colorless liquid (86% yield); IR ν(neat) 2910, 2840, 1720, 1450, 1370,1155 cm⁻¹ ; NMR-60 δ(CDCl₃) 1.30 (s, 17H), 1.1-2.0 (m, 4H), 2.30(t,J=6.0 Hz, 2H), 3.33 (t, J=6.0 Hz, 2H), 4.11 (s, 2H), 4.40 (AB systemΔν=8.0, J=6.0 Hz, 4H).

General Procedure for Ortho Ester Formation (scheme 4 A)

To a solution of bromo ester (3.4-14.2 mmol) in dry CH₂ Cl₂ (10-40 ml)at 0° C. was added with stirring distilled boron trifluoride etherate(0.85-3.55 mmol). After 4 h at 0° C., reaction mixture was quenched bythe addition of triethylamine (3.4-14.2 mmol), diluted with diethyletherand filtered to remove the amine-BF₃ complex. The filtrate wasevaporated and residue was purified by chromatography(hexane-ethylacetate-triethylamine/80:20:1, v/v/v) to give bromo orthoester.

1-(5'-bromo pentanyl)-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane 19.Colorless oil (68% yield); IR ν(neat) 2940, 2915, 2855, 1450, 1390,1050, 980 cm⁻¹ ; NMR-60 δ(CDCl₃) 0.79 (s, 3H), 1.2-2.0 (m, 8H), 3.35 (t,J=6.0 Hz, 2H), 3.87 (s, 6H); MS m/e (rel. intensity) 280 (M⁺, 0.2), 278(M⁺, 0.2), 250 (8.1), 248 (8.5), 197 (7.2), 195 (7.7), 179 (58), 177(61), 72 (54), 69 (100).

1-(8'-bromo octanyl)-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane (20).Amorphous white solid (69% yield); IR ν(KBr) 2940, 2900, 2840, 1450,1390, 1045, 985, 950cm⁻¹ ; NMR-60 δ(CDCl₃) 0.80 (s, 3H), 1.33 (s, 8H),1.0-2.1 (m, 6H), 3.40 (t, J=6.0 Hz, 2H), 3.93 (s, 6H); MS m/e (rel.intensity) 323 (M⁺, 2.1), 321 (M⁺, 2.0), 292 (4.4), 290 (5.1), 239(8.6), 237 (7.1), 221 (34), 219 (33), 69 (71), 55 (100).

1-(10'-bromo decanyl)-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane (21).White solid (74% yield); m.p. 51°-53° C.; IR ν(KBr) 2940, 2900, 2850,2830, 1455, 1390, 1055, 985, 955 cm⁻¹ ; NMR-60 δ(CDCl₃) 0.80 (s, 3H),1.27 (s, 12H), 1.1-2.1 (m, 6H), 3.39 (t, J=6.0 Hz, 2H), 3.87 (s, 6H); MSm/e (rel. intensity) 350 (M⁺, 1.2), 348 (M⁺, 1.1), 321 (3.0), 319 (7.6),269 (7.5), 248 (97), 144 (37), 55 (100).

1-(11'bromo undecananyl)-4-methyl-2,6,7-trioxabicyclo[2,2,2]octane (22).White solid (76%, yield); m.p. 47.5°, 48.5° C.; IR ν(KBr) 2900, 2835,1460, 1045, 975 cm⁻¹ ; NMR-60 δ(CDCl₃) 0.79 (s, 3H), 1.25 (s, 14H),1.1-2.1 (m, 6H), 3.37 (t, J=6.0 Hz, 2H), 3.85 (s, 6H); MS m/e (rel.intensity) 364 (M⁺, 3.5), 362 (M⁺, 3.4), 334 (13), 332 (13), 283 (15),263 (85), 261 (97), 144 (51), 55 (100).

4. Preparation of 17α-aklynylamide estradiols (scheme 4B)

General Procedure for Coupling Reaction

In a flame-dried flask under argon atmosphere, 3,17β-bistetrahydropyranyl ethinylestradiol 23 (1.5 mmol) synthesized fromcommercial ethynyl estradiol and dihydropyran was dissolved in dry THF(40 ml) and HMPA (6.0 mmol). The solution was cooled at -78° C. andn-BuLi

(3.0 mmol) was added. After 2 h, appropriate bromo ortho ester 19-22(6.0 mmol) in dry THF (10 ml) was added at -78° C. The mixture wasallowed to return slowly at room temperature and keeped at thistemperature overnight. Then, brine was added and the reaction mixturewas extracted with ethylacetate. The organic phase was dried over MgSO₄and the solvent was removed under reduced pressure. The crude productwas purified by chromatography (hexane-ethylacetate-triethylamine/96:4:1to 50:1, v/v/v) to give coupling product 24-27, unreacted steroid 23(61, 22, 57%) and small quantity of undeterminated product.

1-{3',17'β-bis[(tetrahydro-2"H-pyran-2"yl)oxy]estra-1',3',5'(10')-trien-17'α-yl}-7-(4'-methyl-2',6',7'-trioxabicyclo[2'.2'.2']octan-1'-yl)-1-heptyne(24). Colorless oil (15% yield); IR ν(neat) 2920, 2855, 2230 w, 1600,1485 cm⁻¹ ; NMR-60 δ(CDCl₃) 0.75 (s, 3H), 0.88 (s, 3H), 2.80 (m, 2H),3.2-4.1 (m, 4H), 3.80 (s, 6H), 4.9-5.3 (m, 1H), 5.34 (s, 1H), 6.75 (m,2H), 7.19 (d, J=8.0 Hz, 1H); MS m/e (rel. intensity) 579 (M⁺ -DHP, 4.0),564 (1.1), 494 (12), 477 (12), 374 (13), 85 (100).

1-{3',17'β-bis[(tetrahydro-2"H-pyran-2"yl)oxy]estra-1',3',5'(10')-trien-17'α-yl}-10-(4'methyl-240.6'.7'-trioxabicyclo[2'.2'.2']octan-1'-yl)-1-decyne (25). Colorless oil(15% yield); IR ν(neat) 2915, 2850, 210 w, 1600, 1485 cm⁻¹ ; NMR-200δ(CDCl₃) 0.79 (s, 3H), 0.90 (s, 3H), 2.24 (t, J=6.6 Hz, 2H), 2.83 (m,2H), 3.55 (m, 2H), 3.89 (s, 6H), 3.95 (m, 2H), 4.98 and 5.19 (2s, 1H),5.39 (s, 1H), 6.78 (d, J=2.6 Hz, 1H), 6.84 (dd, J₁ =2.6 Hz and J₂ =8.4Hz, 1H), 7.22 (d, J=8.4 Hz, 1H); MS m/e (rel. intensity) 620 (M⁺ -DHP,4.8), 535 (13), 518 (8.9), 85 (100).

1-[3',17'β-bis[(tetrahydro-2"H-pyran-2"yl)oxy]estra-1',3',5'(10')-trien-17'α-yl}-12-(4'methyl-2',6',7'-trioxabicyclo[2'.2'.2']octan-1-yl)-1-dodecyne(26). Colorless visquous oil (42% yield); IR ν(neat) 2920, 2850, 2210vw, 1600, 1485 cm⁻¹ ; NMR-200 δ(CDCl₃) 0.79 (s, 3H), 0.90 (s, 3H), 2.25(t, J=6.6 Hz, 2H), 2.83 (m, 2H), 3.55 (m, 2H), 3.89 (s, 6H), 3.95 (m,2H), 5.0 and 5.2 (2s, 1H), 5.39 (s, 1H), 6.78 (d, J=2.6 Hz, 1H), 6.84(dd, J₁ =2.6 Hz and J₂ =8.4 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H); MS m/e(rel. intensity) 649 (M⁺ -DHP, 6.1), 634 (0.7), 564 (22), 547 (16), 85(100).

1-{3',17'β-bis[(tetrahydro-2"H-pyran-2"yl)oxy]estra-1'3'5'(10')-trien-1-17'α-yl}-13-(4'methyl-2',6',7'-trioxabicyclo[2'.2'.2']octan-1'yl)-1-tridecyne (27). Colorless visquous oil (35% yield); IR ν(neat) 2915, 2850,2290 vw, 1600, 1490 cm⁻¹ ; NMR-200 δ(CDCl₃) 0.80 (s, 3H), 0.90 (0.3H),2.25 (t, J=6.6 Hz, 2H), 2.83 (m, 2H), 3.53 (m, 2H), 3.89 (s, 6H), 3.95(m, 2H), 5.0 and 5.2 (2s, 1H), 5.39 (s, 1H), 6.78 (d, J=2.2 Hz, 1H),6.84 (dd, J₁ =2.6 and J₂ =8.4 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H).

General Procedure for Ortho Ester and di-THP Hydrolysis

The product with ortho ester and di-THP group (0.22-0.63 mmol) wasdissolved in MeOH (80-120 ml) and p-toluenesulfonic acid (0.17-0.23mmol) was added. The solution was stirred at room temperature for 2-3 h.Then, water was added, MeOH was removed under reduced pressure andresidue was extracted with ethylacetate. After evaporation of solvent,the crude product was purified by column chromatography(hexane-ethylacetate/5:5, v/v) to give ester compound with free hydroxylgroup.

8-(3',17'β-dihydroxy estra-1',3',5'(10')-trien-17'α-yl)-7-octynoateester of 2', 2'-dihydroxymethyl propanol (28). Colorless visquous oil(70% yield); IR ν(film) 3340, 2910, 2850, 1710, 1600, 1485 cm⁻¹ ;NMR-200 δ(CDCl₃) 0.83 (s, 3H), 0.86 (s, 3H), 2.27 (t, J=6.4 Hz, 2H), (t,J=7.1 Hz, 2H), 2.81 (m, 2H), 3.54 (s broad, 4H), 4.17 (s, 2H), 4.87 (s,1H), 6.56 (d, J=2.6 Hz, 1H), 6.63 (dd, J₁ =2.6 Hz and J₂ =8.4 Hz, 1H),7.17 (d, J=8.4 Hz, 1H); MS m/e (rel. intensity) 512 (M⁺, 14), 494 (97),479 (17), 466 (11), 270 (48), 159 (100).

11-(3',17'β-dihydroxy estra-1',3',5'(10')-trien-17'α-yl)-10-undecynoateester of 2',2'-dihydroxymethyl propanol (29). Colorless visquous oil(61% yield); IR ν(neat) 3360, 2910, 2840, 2210 vw, 1710, 1600, 1485 cm⁻¹; NMR-200 (CDCl₃) δ0.84 (s, 3H), 0.86 (s, 3H), 2.24 (t, J=7.0 Hz, 4H),2.79 (m, 2H), 3.34 (s broad, 2H), 3.56 (s broad, 4H), 4.13 (s, 2H), 6.57(s_(app), 1H), 6.63 (dd, J₁ =2.6 Hz and J₂ =8.4 Hz, 1H), 7.14 (d, J=8.4Hz, 1H) MS m/e (rel. intensity) 554 (M⁺, 5.0), 536 (57), 520 (10), 507(7.6), 435 (14), 419 (20), 270 (39), 160 (85), 133 (100).

13-(3',17'β-dihydroxy estra-1',3',5'(10')-trien-17'α-yl)-12-tridecynoateester of 2',2'-dihydroxymethyl propanol (30). Colorless visquous oil(78% yield); IR ν(film) 3360, 2915, 2840, 1710, 1600, 1490 cm⁻¹ ;NMR-200 δ(CDCl₃) 0.83 (s, 6H), 2.25 (m, 4H), 2.78 (m, 2H), 3.53 (sbroad, 4H), 4.09 (s, 2H), 6.6 (m, 2H), 7.10 (d, J=8.0 Hz, 1H); MS m/e(rel. intensity) 582 (M⁺, 1.0), 563 (38), 548 (5.7), 535 (3.5), 463(5.7), 446 (13), 270 (44), 160 (57), 133 (58), 55 (100).

14-(3',17'β-dihydroxyestra-1',3',5'(10')-trien-17'α-yl)-I3-tetradecynoate ester of2',2'-dihydroxymethyl propanol (31). Colorless visquous oil (83%,yield); IR ν(film) 3360, 2910, 2840, 2220 vw, 1710, 1605, 1490 cm⁻¹ ;NMR-200 δ(CDCl₃) 0.85 (s, 3H), 0.87 (s, 3H), 2.25 (t, J=6.6 Hz, 2H),2.33 (t, J=7.1 Hz, 2H), 2.80 (m, 2H), 2.9 (m, 2H), 3.58 (s broad, 4H),4.20 (s, 2H), 5.72 (s, 1H), 6.56 (d, J=2.6 Hz, 1H), 6.62 (dd, J₁ =2.6 Hzand J₂ =8.4 Hz, 1H), 7.15 (d, J=8.8 Hz, 1H).

General Procedure for Hydrolysis of Ester Following by Amide Formation

At a solution of ester (0.14-0.49 mmol) in MeOH (12-50 ml) was addedaqueous solution of KOH 10% w/v (6-25 ml) and mixture was refluxed underargon atmosphere for 24 h. Thereafter, water was added and MeOH wasevaporated under reduced pressure. The resulting solution was acidifiedwith HCl and extracted with ethylacetate. Organic phase was washed withwater, brine and dried over MgSO₄. Without purification, the crudecarboxylic acid (IR acid band at 1700 and 2400-3600 cm⁻¹) was dissolvedin dry CH₂ Cl₂ (20-70 ml) and tributylamine (0.58-2.04 mmol). Themixture was cooled at -10° C., isobutyl chloroformate (0.68-2.41 mmol)was added and allowed to react 30 min. At this time, N-methylbutylaminein excess (4.2-16.0 mmol) was added and the cooling bath was removed.After 2 h, CH₂ Cl₂ was added and organic phase was washed with HCl (1N)and dried over MgSO₄. The solvent was removed and crude amide purifiedby column chromatography (hexane-ethylacetate/7:3, v/v).

N-butyl, N-methyl-8-[3'-(i-butyloxy carbonyloxy)-17'β-hydroxyestra-1',3',5'(10')-trien-17'α-yl]-7-octynamide (32). Colorless oil (79%yield); IR ν(neat) 3380, 2920, 2850, 1745, 1620 cm⁻¹ ; NMR-200 δ(CDCl₃)0.87 (s, 3H), 0.91 and 0.94 (2t, J=7.3 Hz, 3H), 1.00 (d, J=6.6 Hz, 6H),2.85 (m, 2H), 2.89 and 2.91 (2s, 3H), 3.22 and 3.33 (2t, J=7.5 Hz, 2H),4.02 (d, J=7.0 Hz, 2H), 6.88 (d, J=2.6 Hz, 1H), 6.93 (dd, J₁ =2.6 Hz andJ₂ =8.4 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H); MS m/e (rel. intensity) 579(M⁺, 12), 561 (26), 546 (11), 461 (6.7), 447 (3.7), 270 (84), 57 (100).EMS M⁺ calculated for C₃₆ H₅₃ O₅ N: 579.3923; found: 79.3970.

N-butyl, N-methyl-11-[3'-(i-butyloxy carbonyloxy)-17'β-hydroxyestra-1',3',5'(10')-trien-17'α-yl]-10-undecynamide (33). Colorless oil(67% yield); IR ν(neat) 3370, 2910, 2840, 1745, 1620 cm⁻¹ ; NMR-200δ(CDCl₃) 0.87 (s, 3H), 0.92 and 0.95 (2t, J=6.6 Hz, 3H), 1.00 (d, J=7.0Hz, 6H), 2.86 (m, 2H), 2.90 and 2.94 (2s, 3H), 3.24 and 3.35 (2t, J=7.3Hz, 2H), 4.03 (d, J=6.6 Hz, 2H), 6.88 (d, J=2.6 Hz, 1H), 6.93 (dd, J₁=2.6 Hz and J₂ =8.8 Hz, 1H), 7.30 (d, J=8.1 Hz, 1H); MS m/e (rel.intensity) 621 (M⁺, 2.1), 606 (2.4), 602 (6.2), 212 (43), 159 (69), 142(68), 114 (100).

N-butyl, N-methyl-13-[3'(i-butyloxy carbonyloxy)-17'β-hydroxyestra-1',3',5'(10')-trien-17'α-yl]-12-tridecyamide (34). Colorless oil(89% yield); IR ν(neat) 3370, 2920, 2840, 1745, 1620 cm⁻¹ ; NMR-200δ(CDCl₃) 0.87 (s, 3H), 0.92 and 0.95 (2t, J=7.0 Hz, 3H), 1.00 (d, J=7.0Hz, 6H), 2.86 (m, 2H), 2.90 and 2.96 (2s, 3H), 3.25 and 3.35 (2t, J=7.4Hz, 2H), 4.02 (d, J=6.6 Hz, 2H), 6.88 (d, J=2.2 Hz, 1H), 6.93 (dd, J₁=2.6 Hz and J₂ =8.4 Hz, 1H), 7.30 (d, J=8.8 Hz, 1H); MS m/e (rel.intensity) 649 (M⁺, 20), 633 (15), 631 (18), 616 (8.2), 531 (15), 516(5.6), 270 (85), 57 (100); EMS M⁺ calculated for C₄₁ H₆₃ O₅ N: 649.4706;found: 649.4643.

N-butyl, N-methyl-14-[3'(i-butyloxy carbonyloxy)-17'β-hydroxyestra-1',3',5'(10')-trien-17'α-yl]-13-tetradecynamide (35). Colorlessoil (83%, yield); IR ν(neat) 3380, 2910, 2840, 1750, 1625 cm⁻¹ ; NMR-200δ(CDCl₃) 0.87 (s, 3H), 0.92 and 0.95 (2t, J=7.0 Hz, 3H), 1.00 (d, J=6.6Hz, 6H), 2.85 (m, 2H), 2.91 and 2.96 (2s, 3H), 3.25 and 3.36 (2t, J=7.4Hz, 2H), 4.03 (d, J=6.6 Hz, 2H), 6.88 (d, J=2.6 Hz, 1H), 6.93 (dd, J₁=2.9 Hz and J₂ =8.4 Hz, 1H), 7.30 (d, J=8.8 Hz, 1H); MS m/e (rel.intensity) . . . .

Hydrolysis of Carbonate

Hydrolysis of carbonate compounds 32-35 was performed as follows:carbonate derivatives were dissolved in methanol (10 ml) K₂ CO₃ (1%;p/v) in aqueous methanol (25:75, v/v) (10 ml) was added and theresulting solution was stirred at room temperature for 3h. Reactionmixture was acidified with HCl (1N) and MeOH was evaporated undervacuum. The residue was extracted with ethyl acetate and organic phasewas dried, evaporated and purified by column chromatography(hexane-ethylacetate) 6.5:3.5, v/v).

N-butyl, N-methyl-8-[3',17'β-dihydroxyestra-1',3',5'(10')-trien-17'α-yl]-7-octynamide ("EM 157"). Purified bycolumn chromatography (hexane-ethylacetate/4:6, v/v). Amorphous whitesolid (88% yield); IR ν(film) 3280, 2910, 2840, 1610 cm⁻¹ ; NMR-200δ(CDCl₃) 0.87 (s, 3H), 0.91 and 0.94 (2t, J=7.0 Hz, 3H), 2.80 (m, 2H),2.90 and 2.92 (2s, 3H), 3.22 and 3.34 (2t, J=7.3 Hz, 3H), 5.22 (s, 1H),6.57 (d, J=2.9 Hz, 1H), 6.64 (dd, J₁ =2.6 Hz and J₂ =8.4 Hz, 1H), 7.16(d, J=8.4 Hz, 1H); MS m/e (rel. intensity) 479 (M⁺, 11), 462 (18), 460(38), 446 (18), 270 (30), 114 (56), 88 (67), 44 (100); EMS M⁺ calculatedfor C₃₁ H₄₅ O₃ N: 479.3399; found: 479.3369.

N-butyl, N-methyl-11-[3',17'β-dihydroxyestra-1',3',5'(10')-trien-17'α-yl)-10-undecynamide ("EM 183"). Purifiedby column chromatography (hexane-ethylacetate/4: 6, v/v). Amorphouswhite solid (83% yield); IR ν(KBr) 3300, 2910, 2840, 1610 cm⁻¹ ; NMR-200δ(CDCl₃) 0.87 (s, 3H), 0.93 and 0.95 (2t, J=7.0 Hz, 3H), 2.80 (m, 2H),2.91 and 2.94 (2s, 3H), 3.23 and 3.35 (2t, J=7.3 Hz, 2H), 5.30 (s, 1H),6.57 (d, J=2.6 Hz, 1H), 6.64 (dd, J₁ =2.6 Hz and J₂ =8.4 Hz, 1H), 7.16(d, J=8.1 Hz, 1H); MS m/e (rel. intensity) 521 (M⁺, 4.4), 505 (10), 502(26), 489 (7.7), 487 (8.7), 270 (20), 114 (55), 88 (42), 44 (100).

N-butyl, N-methyl-13-[3',17'β-dihydroxyestra-1',3',5'(10')-trien-17'α-yl]-12-tridecynamide ("EM 163"). Purifiedby column chromatography (hexane-ethylacetate/7:3, v/v). Amorphous whitesolid (98% yield); IR ν(film) 3300, 2910, 2840, 1610 cm⁻¹ ; NMR-200δ(CDCl₃) 0.88 (s, 3H), 0.93 and 0.95 (2t, J=7.0 Hz, 3H), 2.80 (m, 2H),2.93 and 2.97 (2s, 3H), 3.25 and 3.38 (2t, J=7.5 Hz, 2H), 6.61 (d, J=2.6Hz, 1H), 6.69 (dd, J₁ =2.6 Hz and J₂ =8.6 Hz, 1H), 6.87 (s, 1H), 7.14(d, J=8.1 Hz, 1H); MS m/e (rel. intensity) 549 (M⁺, 8.7), 532 (17), 530(23), 516 (12), 270 (30), 114 (35), 88 (45), 44 (100); EMS M⁺ calculatedfor C₃₆ H₅₅ O₃ N: 549.4182, found: 549.4271.

N-butyl, N-methyl-14-[3',17'β-dihydroxyestra-1',3',5'(10')-trien-17'α-yl]-13-tetradecynamide ("EM 196").Purified by column chromatography (hexane-ethylacetate/6:4, v/v).Amorphous white solid (93% yield); IR ν(film) 3280, 2915, 2840, 1615cm⁻¹ ; NMR-200 δ(CDCl₃) 0.88 (s, 3H), 0.94 and 0.95 (2t, J=7.0 Hz, 3H),2.80 (m, 2H), 2.95 and 2.98 (2s, 3H), 3.26 and 3.39 (2t, J=7.3 Hz, 2H),6.61 (d, J=2.2 Hz, 1H), 6.70 (dd, J₁ =2.6 Hz and J₂ =8.4 Hz, 1H), 7.13(m, 2H: aromatic and phenolic hydrogen). ##STR42##

EXAMPLE 6

N-n-butyl, N-methyl-(3'-17'β-dihydroxy-11'β-methoxy estra1',3',5'(10')-trien 7'α-yl) undecanamide ("EM 111") and its 17β-ethinylderivatives ("EM 121"). ##STR43##

EXAMPLE 6 A 11β-chloromethyl derivatives

N-N-butyl, n-methyl, (11β-chloromethyl-3',17'β-dihydroxy-estra-1',3',5(10')-trien-7'α-yl) undecanamide (56). and its 17α-ethinyl derivative(58). ##STR44##

EXAMPLE 7 Compounds with aliphatic side-chain in 17α-position

N-n-butyl, n-methyl, 17'β-hydroxy-3'-methoxyestra-1',3',5',(10')-trien-17α'α-yl) undecanamide ("EM 103"). ##STR45##

EXAMPLE 8 17α-cyclopropyl derivatives

N-n-butyl, N-methyl-(17'α-cyclopropyl-3',17β-dihydroxyestra-1',3',-5',(10)-trien-7'α-yl) undecanamide (68) and its17'α-chlorocyclopropyl and 17'α-fluorocyclopropyl derivative (69).##STR46##

EXAMPLE 9

N-n-butyl, N-methyl-(17'α-cyclopropyl-3',17β-dihydroxy 11'β-methoxyestra 1',3',5',(10)-trien-7'α-yl) undecanamide (70 X=H) and its17'α-chlorocyclopropyl and 17'α-fluorocyclopropyl derivative (70, X=F,Cl).

Same example as Example 8 with compound 49 as starting material.##STR47##

EXAMPLE 10 17α-cyanovinyl derivatives

N-n-butyl, N-methyl-(17'α-cyclopropyl-3',17β-dihydroxy 11'β-methoxyestra 1',3',5',(10)-trien-7'α-yl) undecanamide (73). ##STR48##

EXAMPLE 11 Compounds with aliphatic side chain in 15α-position

N-n-butyl, N-methyl-(3',17β-dihydroxy 17'α-ethinyl estra1',3',5',(10)-trien-15'α-yl) undecanamide ("EM 108"). ##STR49##

EXAMPLE 12 17α-thioethyl derivatives

N-n-butyl, N-methyl-(3',17β-dihydroxy 17'α-thioethyl estra1',3',-5',(10)-trien-7'α-yl) undecanamide (82) and its ethyl disulfitederivative (83). ##STR50##

EXAMPLE 13 17α-thiopropyl derivatives

N-n-butyl, N-methyl-(3',17β-dihydroxy 17'α-thiopropylestra-1',3',5'-derivatives (10')-trien-7'α-yl) undecanamide (84) and itsethyl disulfite derivative (86). ##STR51##

EXAMPLE 14 11β-ethyl derivatives

N-n-butyl, N-methyl-(3',17β-dihydroxy 17'α-ethinoyl-11β-ethyl estra1',3',5'(10')trien-7'α-yl) undecanamide (97). ##STR52##

EXAMPLE 15 14,15 epoxide derivatives

N-n-butyl, N-methyl-(3',17β-dibenzoyl-14',15'-epoxy-estra1',3',5'(10')trien-7'α-yl) undecanamide ("EM 180") and ("EM 181").##STR53##

EXAMPLE 16

N-n-butyl, N-methyl-11-(3',17'α-dihydroxyestra-1',3',5'(10')trien-7'α-yl) undecanamide ("EM 187") ##STR54##

EXAMPLE 17

N-n-butyl, N-methyl-11-(6'-hydroxy-2'-(4"-hydroxyphenyl)-3'-ethyl-indol-N'-yl) undecanamide (104).

The starting material 101 has been synthesized as described by VonAngerer et al., J. Med. Chem. 27: 1439-1447, 1984. ##STR55##

EXAMPLE 18

N-n-butyl,N-methyl-11-(6'-hydroxy-2'-(4"-hydroxyphenyl)-(1',2'-dehydronaphtalen-3'-yl)undecanamide (110). ##STR56##

EXAMPLE 19

N-n-butyl, N-methyl-11-[4,4'-(1,2-diethyl-1,2-ethanydyl)bis-phenol-3-yl) undecanamide (115) ##STR57##

Other sex steroid activity inhibitors in accordance with the inventionsmay be synthesized by methods known in the art, by methods analogous tothose set forth above and by modifying the synthesis set fort above in amanner known in the art.

The terms and descriptions used here are preferred embodiment set-forththe way of illustration only and are not intended as limitations on themany variations which those of skill in the art will recognize to bepossible in practicing the present invention as defined by the followingclaims.

What is claimed is:
 1. A pharmaceutical composition comprising apharmaceutically acceptable diluent or carrier and a therapeuticallyeffective amount of a sex steroid activity inhibitor having, as part ofits molecular structure, a substituted or unsubstituted estrogenicnucleus of structure I ##STR58## wherein the dotted lines representoptional pi bonds and wherein said compound includes as another part ofits molecular structure a side chain substituted onto a ring carbon ofsaid structure I represented by the formula --R¹ [--B--R² --]_(x) L--Gwherein at least one of said side chains is substituted at carbon 16,wherein:x is an integer from 0 to 6, wherein at least one of L and G isa polar moiety distanced from said ring carbon by at least threeintervening atoms, and wherein: R¹ and R² are independently eitherabsent or selected from the group consisting of straight- orbranched-chain alkylene, straight- or branched-chain alkynylene,straight- or branched-chain alkenylene, phenylene, andfluoro-substituted analogs of the foregoing; B is either absent orselected from the group consisting of --O--, --CR³ OR³ --, and phenylene(R³ being hydrogen or lower alkyl); L is selected from the groupconsisting of lower alkyl, --CONR⁴ --, --CSNR⁴ --, --NR⁵ CO--, --NR⁵CS--, --NR⁵ CONR⁴ --, --SO₂ NR⁴ --, --NR⁵ SO₂ --, --NR⁴ --, --S--,--SO-- --SO₂ -- (R⁴ and R⁵ being independently selected from the groupconsisting of hydrogen, lower alkyl, and a derivative of the foregoingwhich, together with G forms a 5-7 member nitrogen hetero ring; and G isselected from the group consisting of hydrogen, lower alkyl, loweralkenyl, lower alkynyl, (C₃ -C₇)cyclo-alkyl, bromo(lower)alkyl,chloro(lower)alkyl, fluoro(lower)alkyl, iodo(lower)alkyl,(lower)alkoxycarbonyl(lower)alkyl, (C₅ -C₁₀)aryl, (C₇ -C₁₁)arylkyl,di(lower)alkylamino(lower)alkyl, fluoro-substituted analogs of theforegoing, and a derivative of the foregoing thereof which, togetherwith L forms a 5-7 member nitrogen hetero ring.
 2. The pharmaceuticalcomposition of claim 1 wherein said structure I includes 15,16insaturation.
 3. The pharmaceutical composition of claim 1 wherein saidstructure I includes 14,15 insaturation.
 4. The pharmaceuticalcomposition of claim 1 wherein said structure I includes an alkynylsubstitution at the 17α-position.
 5. The pharmaceutical composition ofclaim 1 wherein said structure includes a hydroxyl or keto substitutionat the 17 position.
 6. A sex steroid activity inhibiting compoundhaving, as part of its molecular structure, a substituted orunsubstituted estrogenic nucleus of structure I: ##STR59## wherein thedotted lines represent optional pi bonds and wherein said compoundincludes as another part of its molecular structure a side chainsubstituents onto a ring carbon of said general structure I representedby the formula --R¹ [--B--R² --]_(x) L--G wherein at least one of saidside chains is substituted at carbon 16 wherein:x is an integer from 0to 6, wherein at least one of L and G is polar moiety distanced fromsaid ring carbon by at least three intervening atoms, and wherein: R¹and R² are independently either absent or selected from the groupconsisting of straight- or branched-chain alkylene, straight- orbranched-chain alkynylene, straight- or branched-chain alkenylene,phenylene, and fluoro-substituted analogs of the foregoing; B is eitherabsent or selected from the group consisting of --O--, and phenylene (R³being hydrogen or lower alkyl); L is either a moiety which together withG, forms a heterocyclic ring having at least one nitrogen atom or isselected from the group consisting of lower alkyl, --CONR⁴ --, --CSNR⁴--, --NR⁵ CO--, --NR⁵ CS--, --NR⁵ CONR⁴ -- --NR⁵ SO₂ --, --NR⁴ --,--S--, --SO-- and --SO₂ -- (R⁴ and R⁵ being independently selected fromthe group consisting of hydrogen and lower alkyl; and G is either amoiety which together with L forms a heterocyclic ring having at leastone nitrogen atom or is selected from the group consisting of hydrogen,lower alkyl, lower alkenyl, lower alkynyl, (C₃ -C₇)cycloalkyl,bromo(lower)alkyl, chloro(lower)alkyl, fluoro(lower)alkyl,iodo(lower)alkyl, cyano(lower)alkyl, carboxy(lower)alkyl,(lower)alkoxycarbonyl(lower)alkyl, (C₆ -C₁₀)aryl, (C₇ -C₁₁)arylalkyl,di(lower)alkylamino(lower)alkyl, fluoro-substituted analogs of theforegoing.
 7. A method for inhibiting sex steroid activity comprisingadministering to a human or other warm-blooded animal in need of suchtreatment, with or without additional diluent or carrier, apharmaceutically effective amount of a compound selected from the groupconsisting of ##STR60## wherein R³ and R¹⁷ are independently selectedfrom the group consisting of H-- and C₆ H₅ C(O).
 8. A method fortreating an estrogen-related disease comprising administering to apatient afflicted with said disease in need of such treatment, with orwithout additional diluent or carrier, a pharmaceutically effectiveamount of a compound selected from the group consisting of ##STR61##wherein R³ and R¹⁷ are independently selected from the group consistingof H-- and C₆ H₅ C(O).
 9. A method for treating an androgen-relateddisease comprising administering to a patient afflicted with saiddisease in need of such treatment, with or without additional diluent orcarrier, a pharmaceutically effective amount of a compound selected fromthe group consisting of ##STR62## wherein R³ and R¹⁷ are independentlyselected from the group consisting of H-- and C₆ H₅ C(O).
 10. Thepharmaceutical composition of claim 1 wherein structure I includes a 11substitution selected from the group consisting of lower alkyl, loweralkenyl, lower alkynyl, (C₆ -C₁₀)aryl, alkyl sulfonyl, aryl sulfonyl, a5 to 7-member heterocyclic ring having at least one hetero atom,--(CH₂)_(s) W (W is being nitrile, hydroxyl, azido, nitroso, nitro,thionitrile, halogen, alkyl sulfonyl, aryl sulfonyl and s is an integerfrom 1 to 6), --OR₂₆ (R₂₆ being --Se--, NR₂₆, --S-- or --O--, and R₂₇being hydrogen or lower alkyl), ═S, ═NR₂₈ and ═NOR₂₈ (R₂₈ beinghydrogen, lower alkyl or (C₁ -C₇)alkanyl).
 11. The pharmaceuticalcomposition of claim 1 wherein said structure I includes 16-pi-bondedlower halogenated alkyl.
 12. A pharmaceutical composition comprising apharmaceutically acceptable diluent or carrier and a therapeuticallyeffective amount of a sex steroid activity inhibitor having, as part ofits molecular structure, a substituted or unsubstituted nucleus selectedfrom the group consisting of: ##STR63## wherein said compound includesas another part of its molecular structure a side chain substitution ofthe formula --R¹ [--B--R² --]_(x) L--G wherein:x is an integer from 0 to6, wherein at least one of L and G is a polar moiety distanced from saidring carbon by at least three intervening atoms, and wherein: R¹ and R²are independently either absent or selected form the group consisting ofstraight- or branched-chain alkylene, straight- or branched-chainalkynylene, straight-or branched-chain alkenylene, phenylene, andfluoro-substituted analogs of the foregoing; B is either absent orselected from the group consisting of --O--, --CR³ OR³ --, and phenylene(R³ being hydrogen or lower alkyl); L is selected from the groupconsisting of lower alkyl, --CONR⁴ --, --CSNR⁴ --, --NR⁵ CO--, --NR⁵CS--, --NR⁵ CONR⁴ --, --O--, --NR⁴ --, --S--, --SO-- and --SO₂ -- and aderivative of the foregoing which, together with G, forms a 5-7 memberednitrogen hetero ring (R⁴ and R⁵ being independently selected from thegroup consisting of hydrogen, lower alkyl; and R⁶ being selected fromthe group consisting of hydrogen, nitrile and nitro); and G is selectedfrom the group consisting of hydrogen, lower alkyl, lower alkenyl, loweralkynyl, (C₃ -C₇)cycloalkyl, bromo(lower)alkyl, chloro(lower)alkyl,fluoro(lower)alkyl, iodo(lower)alkyl, cyano(lower)alkyl,carboxy(lower)alkyl, (lower)alkoxycarbonyl(lower)alkyl, (C₆ -C₁₀)aryl,(C₇ -C₁₁)arylalkyl, di(lower)alkylamino(lower)alkyl, fluoro-substitutedanalogs of the foregoing, and a derivative of the foregoing which,together with L, form a 5-7 membered nitrogen hetero ring.
 13. Thepharmaceutical composition of claim 12 wherein said nucleus includes anethynyl substitution at 17α.
 14. A sex steroid inhibiting compoundhaving, as part of its molecular structure, a substituted orunsubstituted nucleus selected from the group consisting of: ##STR64##wherein said compound includes as another part of its molecularstructure a side chain substitution of the formula --R¹ [--B--R² --]_(x)L--G wherein:x is an integer from 0 to 6, wherein at least one of L andG is a polar moiety distanced from said ring carbon by at least threeintervening atoms, and wherein: R¹ and R² are independently eitherabsent or selected form the group consisting of straight- orbranched-chain alkylene, straight- or branched-chain alkynylene,straight-or branched-chain alkenylene, phenylene, and fluoro-substitutedanalogs of the foregoing: B is either absent or selected from the groupconsisting of --O--, --CR³ OR³ --, and phenylene (R³ being hydrogen orlower alkyl); L is selected from the group consisting of lower alkyl,--CONR⁴ --, --CSNR⁴ --, --NR⁵ CO--, --NR⁵ CS--, --NR⁵ CONR⁴ --, --SO₂NR⁴ --, --O--, --NR⁴ --, --S--, --SO-- --SO₂, and a derivative of theforegoing which, together with G, forms a 5-7 membered nitrogen heteroring-(R⁴ and R⁵ being independently selected from the group consistingof hydrogen and lower alkyl; and R⁶ being selected from the groupconsisting of hydrogen, nitrile and nitro); and G is selected from thegroup consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl,(C₃ -C₇)cycloalkyl, bromo(lower)alkyl, chloro(lower)alkyl,fluoro(lower)alkyl, iodo(lower)alkyl, cyano(lower)alkyl,carboxy(lower)alkyl, (lower)alkoxycarbonyl(lower)alkyl, (C₆ -C₁₀)aryl,(C₇ -C₁₁)arylalkyl, di(lower)alkylamino(lower)alkyl, fluoro-substitutedanalogs of the foregoing, and a derivative of the foregoing which formsa 5-7 membered nitrogen hetero ring.
 15. The sex steroid inhibitingcompound of claim 14 wherein said nucleus includes an ethynylsubstitution at 17α.
 16. A pharmaceutical composition comprising apharmaceutically acceptable diluent or carrier and a therapeuticallyeffective amount of at least one sex steroid inhibitor selected from thegroup consistingof:N-n-butyl-N-methyl-11-(3',17'β-dihydroxy-17'α-ethynyl-15'β,16'β-methylene-estra-1',3',5'(10')-trien-7'α-yl) undecanamide ##STR65##N-n-butyl-N-methyl-11-(3', 17'β-dihydroxy-estra-1',3',5'(10'),15'-tetraen-7'α-yl) undecanamide ##STR66## N-n-butyl-N-methyl-11-(3',17'β-dihydroxy-17'α-ethynyl-estra-1',3',5'(10'),14'-tetraen-7'.alpha.-yl)undecanamide ##STR67## N-n-butyl-N-methyl-11-(3',17'β-dihydroxy-estra-1',3',5'(10'), 14'-tetraen-7'α-yl) undecanamide##STR68##N-n-butyl-N-methyl-11-(3',17'β-dihydroxy-15'β,16'β-methylene-estra-1',3',5'(10')-trien-7'α-yl)undecanamide ##STR69##N-n-butyl-N-methyl-11-(3',17'β-dihydroxy-17'α-ethynyl-estra-15'.beta.,16'β-methylene-estra-1',3',5'(10')-trien-7'α-yl) undecanamide ##STR70##17. A pharmaceutical composition comprising a pharmaceuticallyacceptable diluent or carrier and a therapeutically effective amount ofat least one sex steroid inhibitor selected from the group consistingof:N-n-butyl-N-methyl-11-(3'-hydroxy-15'β,16'β-methylene-17'-oxo-estra-1',3',5'(10')-trien-7'α-yl) undecanamide##STR71##N-n-butyl-N-methyl-11-(3',17'β-dibenzoyl-14'β,15'β-epoxy-estra-1',3',5'(10')-trien-7'α-yl)undecanamide ##STR72##N-n-butyl-N-methyl-11-(3',17'β-dibenzoyl-14'α,15'α-epoxy-estra-1',3',5'(10')-trien-7'α-yl)undecanamide ##STR73##
 18. A pharmaceutical composition comprising apharmaceutically acceptable diluent or carrier and a therapeuticallyeffective amount of at least one sex steroid inhibitor selected from thegroup consisting of: ##STR74## wherein R³ and R¹⁷ are independentlyselected from the group consisting of H-- and C₆ H₅ C(O).
 19. A sexsteroid activity inhibiting compound selected from the group consistingof:N-n-butyl-N-methyl-11-(3',17'β-dihydroxy-17'α-ethynyl-15'β,16'β-methylene-estra-1',3',5'(10')-trien-7'α-yl) undecanamide ##STR75##N-n-butyl-N-methyl-11-(3',17'β-dihydroxy-estra-1',3',5'(10'),15'-tetraen-7'α-yl ) undecanamide ##STR76##N-n-butyl-N-methyl-11-(3',17'β-dihydroxy-17'α-ethynyl-estra-1',3',5'(10'),14'-tetraen-7'α-yl) undecanamide ##STR77##N-n-butyl-N-methyl-11-(3',17'β-dihydroxy-estra-1',3',5'(10'),14'-tetraen-7'α-yl) undecanamide ##STR78##
 20. A sex steroid activityinhibiting compound selected from the group consistingof:N-n-butyl-N-methyl-11-(3'-hydroxy-17'-oxo-estra-1',3',5'(10')-15'-tetraen-7'α-yl)undecanamide ##STR79## N-n-butyl-N-methyl-11-(3'-hydroxy-15'β,16'β-methylene-17'-oxo-estra-1',3',5'(10')-trien-7'α-yl) undecanamide##STR80## N-n-butyl-N-methyl-11-(3', 17'β-dibenzoyl-14'β,15'β-epoxy-estra-1',3',5'(10')-trien-7'α-yl) undecanamide ##STR81##N-n-butyl-N-methyl-11-(3',17'β-dibenzoyl-14'α,15'α-epoxy-estra-1',3',5'(10')-trien-7'α-yl)undecanamide ##STR82##
 21. A sex steroid activity inhibiting compoundselected from the group consisting of: ##STR83## wherein R³ and R¹⁷ areindependently selected from the group consisting of H-- and C₆ H₅ C(O).22. A method for treating breast cancer in a human or other warm bloodedpatient in need of such treatment, said method comprising administeringto said patient, with or without additional carrier or diluent, atherapeutically effective amount of the sex steroid activity inhibitingcompound of claim 21.